The antimicrobial protein S100A15 belongs to the S100 family, which is differentially expressed in a variety of normal and pathological tissues. Although the function of S100A15 protein has been ...discussed in several studies, its induction and regulation in oral mucosa, so far, are largely unknown. In this study, we demonstrate that S100A15 is induced by the stimulation of oral mucosa with gram
or gram
bacterial pathogens, as well as with the purified membrane components, namely lipopolysaccharides (LPS) and lipoteichoic acid (LTA). The stimulation of the human gingival fibroblast (GF) and the human mouth epidermal carcinoma (KB) cell lines with either gram
or gram
bacterial pathogens or their purified membrane components (LPS and LTA) results in the activation of NF-κB, apoptosis-regulating kinase1 (ASK1), and MAP kinase signaling pathways including, c-Jun N-terminal kinase (JNK) and p38 together with their physiological substrates AP-1 and ATF-2, respectively. Inhibition of S100A15 by antibodies-mediated Toll-like receptor 4 (TLR4) or Toll-like receptor 2 (TLR2) neutralization reveals the induction of S100A15 protein by LPS/gram
bacterial pathogens to be TLR4- dependent mechanism, whereas induction by LTA/gram
bacterial pathogens to be TLR2- dependent mechanism. Pre-treatment of GF and KB cells with JNK (SP600125), p38 (SB-203580), or NF-κB (Bay11-7082) specific inhibitors further demonstrates the importance of JNK, p38 and NF-κB pathways in the regulation of gram
/gram
bacterial pathogen-induced S100A15 expression. Our data provide evidence that S100A15 is induced in cancer and non-cancer oral mucosa-derived cell lines by gram
/gram
bacterial pathogens and provide insight into the molecular mechanisms by which gram
and gram
bacterial pathogens induce S100A15 expression in the oral mucosa.
Melanoma stem cells (MSCs) are characterized by their unique cell surface proteins and aberrant signaling pathways. These stemness properties are either in a causal or consequential relationship to ...melanoma progression, treatment resistance and recurrence. The functional analysis of CD133
and CD133
cells in vitro and in vivo revealed that melanoma progression and treatment resistance are the consequences of CD133 signal to PI3K pathway. CD133 signal to PI3K pathway drives two downstream pathways, the PI3K/Akt/MDM2 and the PI3K/Akt/MKP-1 pathways. Activation of PI3K/Akt/MDM2 pathway results in the destabilization of p53 protein, while the activation of PI3K/Akt/MKP-1 pathway results in the inhibition of mitogen-activated protein kinases (MAPKs) JNK and p38. Activation of both pathways leads to the inhibition of fotemustine-induced apoptosis. Thus, the disruption of CD133 signal to PI3K pathway is essential to overcome Melanoma resistance to fotemustine. The pre-clinical verification of in vitro data using xenograft mouse model of MSCs confirmed the clinical relevance of CD133 signal as a therapeutic target for melanoma treatment. In conclusion, our study provides an insight into the mechanisms regulating MSCs growth and chemo-resistance and suggested a clinically relevant approach for melanoma treatment.
Recurrence and progression rates vary widely among different histological subtypes of bladder cancer (BC). Normal-appearing mucosa in non-muscle invasive bladder cancer and muscle-invasive bladder ...cancer in cystoscopy and histopathology is a factor in staging and treatment. Telocytes (TCs) are spindle-shaped cells that connect with other cell types allowing communication though cytoskeletal signaling. They are involved in tissue regeneration and pathogenesis of diseases and cancer. In this study, 12 normal-appearing tissues from urinary bladder with BC, both invasive and non-invasive were evaluated in patients who had either trans-urethral resection of bladder tumor or cystectomy. In each case, cystoscopy, intraoperative inspection, and histopathology all confirmed the absence of cancerous elements. Five patients with neurogenic bladder were used as a control group. Immunohistochemistry revealed that c-Kit + cells were intensively distributed in bladder layers from BC samples, while they were seldom detected in the control group. Ultrastructural examination of reprocessed tissue showed an intense distribution of TCs and telopodes in the submucosa and between smooth muscle cells in BC. Telopodes were numerous, arborizing, and intercommunicating. Whereas TCs and telopodes were scarce in the neurogenic bladder. Also, cancerous tissue had the highest expression level of ezrin protein, and this level gradually decreased as we moved away from the tumor. Our finding of TCs number in normal-appearing tissues in conjunction with ezrin expression may compete invasiveness and possibly a trail to reduce recurrence rates.
The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor ...maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma.
Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically ...divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAF
). While the successful targeting of BRAF
does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.
In addition to its contributing role in the development of chronic liver diseases, chronic hepatitis C virus(HCV) infection is associated with extrahepatic manifestations, particularly, ...cutaneous-based disorders including those with pruritus as a symptom. Pruritus is frequently associated with the development of chronic liver diseases such as cholestasis and chronic viral infection, and the accumulation of bile acids in patients’ sera and tissues as a consequence of liver damage is considered the main cause of pruritus. In addition to their role in dietary lipid absorption, bile acids can trigger the activation of specific receptors, such as the G protein-coupled bile acid receptor(GPBA/ TGR5). These types of receptors are known to play a crucial role in the modulation of the systemic actions of bile acids. TGR5 expression in primary sensory neurons triggers the activation of the transient receptor potential vanilloid 1(TRPV1) leading to the induction of pruritus by an unknown mechanism. Although the pathologic phenomenon of pruritus is common, there is no uniformly effective therapy available. Understanding the mechanisms regulating the occurrence of pruritus together with the conduction of large-scale clinical and evidence-based studies, may help to create a standard treatment protocol. This review focuses on the etiopathogenesis and treatment strategies of pruritus associated with chronic HCV infection.
Despite the extensive research that has been conducted to date, practice often differs from established guidelines and will vary between individuals and organisations. It has been noted that the ...global uptake of local and international surgical antimicrobial prophylaxis (SAP) guidelines is poor with limited research investigating factors that affect guideline adherence. The purpose of this systematic review was to determine the reported barriers and enablers to the adherence of SAP guidelines.
A search of the literature was performed using four electronic databases (CINAHL, EMBASE, PubMed and SCOPUS) for articles published in the English language from January 1998 to December 2018. Articles were included if they were solely related to SAP and discussed the barriers or enablers to SAP guideline adherence. Articles that assessed the adherence to a range of infection control measures or discussed adherence to antibiotic treatment guidelines rather than SAP guidelines were excluded from this review. Barriers and enablers were mapped to the Theoretical Domains Framework (TDF). The Mixed Methods Appraisal Tool was used to assess the quality of included studies.
A total of 1489 papers were originally retrieved, with 48 papers meeting the eligibility criteria. Barriers and enablers were mapped to 11 out of 14 TDF domains: knowledge, skills, social/professional role and identity, beliefs about capabilities, beliefs about consequences, reinforcement, memory, attention and decision processes, environmental context and resources, social influences, emotion and behavioural regulation. Barriers were further categorised into personal or organisational barriers, while enablers were arranged under commonly trialled interventions.
There are numerous factors that can determine the uptake of SAP guidelines. An identification and understanding of these factors at a local level is required to develop tailored interventions to enhance guideline adherence. Interventions, when used in combination, can be considered as a means of improving guideline use.
•Effective community engagement and participatory efforts contribute to identifying and rescuing victims of child-trafficking.•Undercover investigation (private investigators) is an alternative ...resort to identifying perpetrators of child trafficking when community efforts fail.•Children rescued from trafficking undergo psychosocial healing processes before they are re-united with their families.•Adapting African indigenous restorative justice systems could facilitate the healing process of survivors of trafficking and make communities conducive for the return of survivors.
Efforts to identify child traffickers, rescue victims of Child Trafficking (CT) and facilitate a smooth reunification of children with their families remain important child protection components of the CT crisis in Ghana. This study utilizes the experiences of practitioners in three (3) regional offices of a Non-Governmental Organization (NGO) – International Needs Ghana, that is at the forefront of implementing national strategies aimed at protecting and safeguarding the welfare of children.
We solicited the views of 15 practitioners involved in CT interventions on the approaches used to identify traffickers and rescue and care for trafficked children in Ghana. Evidence was gathered by means of semi-structured qualitative interviews. Narratives from the practitioners were organized using NVivo and analyzed thematically following reflexive thematic analysis procedures.
The study identified three inter-connected approaches used by practitioners to rescue and protect victims of trafficking. These include the following: 1) community engagements and participatory efforts, 2) The use of private investigators, 3) The provision of aftercare support to rescued children through placing them in care homes where they are prepared for reunification with their families.
Based on these, the findings recommend the intensification of trafficking awareness campaigns in rural communities where education is lacking. The National Commission for Civic Education (NCCE) has been identified as an appropriate national body to spearhead such a mandate. Considering that some traffickers are protected by communities, it is recommended that government and non-profits make efforts at creating awareness in communities about the dangers of shielding traffickers through community durbars and informative sessions during cultural festivities like the “Hogbetsotso” festival, “Asogli Yam Festival”, and the “Odwira” festival. Findings also point to the need for state and non-state institutions to prepare poor families financially for the return of their trafficked children through equipping them with technical and vocational skills like bead making, soap making, weaving and carpentering. Finally, the study recommends the incorporation of trauma-informed treatments in the curriculum training of professionals like social workers and psychologists, to ensure that they provide evidence-based services for children in after-care.
Abstract
Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits, but neuromodulation of aortic baroreceptor afferents remains unexplored for potential translation ...into the clinic. Published studies have used supramaximal stimulations, which are unphysiological and energy inefficient. The objective of the present study was to identify optimal low-charge nerve stimulation parameters that would provide a clinically-relevant (20–30 mmHg) decrease in mean arterial pressure (MAP) in anesthetized spontaneously hypertensive rats. Stimulations of 20 s were delivered to the left aortic depressor nerve (ADN) of these rats using low ranges of pulse amplitudes (≤ 0.6 mA), widths (≤ 0.5 ms) and frequencies (≤ 5 Hz). We also assessed the effects of continuous (20 s)
versus
intermittent (5 s ON/3 s OFF and 5 s ON/3 s OFF for 20 s) stimulation on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance using low (5 Hz) and high (15 Hz) frequencies. Lower pulse amplitudes (0.2 mA) produced 9 ± 2 to 18 ± 2 mmHg decreases in MAP. Higher pulse amplitudes (0.4 mA) produced a median MAP reduction of 28 ± 4 mmHg at 0.2 ms and 5 Hz, with no added benefit seen above 0.4 mA. Continuous and intermittent low frequency stimulation at 0.4 mA and 0.2 ms produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation at 0.4 mA and 0.2 ms produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. We conclude from these findings that “low intensity intermittent” electrical stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents and to evoke a required restoration of MAP levels in spontaneously hypertensive rats. This approach enables low energy consumption and markedly lowers the excessive decreases in MAP and hemodynamic disturbances elicited by continuous high-charge injection protocols.
Key points
•
The medial prefrontal cortex (mPFC) is often referred to as the ‘visceral cortex’, largely based on anatomical connections and cardiovascular influences.
•
Although an extensive ...network of inhibitory interneurons regulates PFC function, their roles in modifying central respiratory, metabolic and cardiac functions have not been explored.
•
This study provides the first integrative investigation describing central respiratory, metabolic and cardiac variables altered following chemical disinhibition of discrete subregions of the mPFC.
•
Changes were evoked in a site‐dependent manner, with central respiratory function modified throughout the mPFC, and exclusively from dorsal regions. By contrast, central respiratory, metabolic and cardiac functions were simultaneously increased in the ventral mPFC, particularly the infralimbic cortex.
•
These data provide reference material for future investigations into chronic changes in the activity of neurons within the mPFC, as seen in stress and mental health disorders, which are often accompanied by autonomic and respiratory dysfunction.
The prefrontal cortex (PFC) is referred to as the visceral motor cortex; however, little is known about whether this region influences respiratory or metabolic outflows. The aim of this study was to describe simultaneous changes in respiratory, metabolic and cardiovascular functions evoked by disinhibition of the medial PFC (mPFC) and adjacent lateral septal nucleus (LSN). In urethane‐anaesthetized rats, bicuculline methiodide was microinjected (2 mm; GABA‐A receptor antagonist) into 90 sites in the mPFC at 0.72–4.00 mm from bregma. Phrenic nerve amplitude and frequency, arterial pressure, heart rate, splanchnic and lumbar sympathetic nerve activities (SNA), expired CO2, and core and brown adipose tissue temperatures were measured. Novel findings included disturbances to respiratory rhythm evoked from all subregions of the mPFC. Injections into the cingulate cortex evoked reductions in central respiratory function exclusively, whereas in ventral sites, particularly the infralimbic region, increases in respiratory drive and frequency, and metabolic and cardiac outflows were evoked. Disinhibition of sites in surrounding regions revealed that the LSN could evoke cardiovascular changes accompanied by distinct oscillations in SNA, as well as increases in respiratory amplitude. We show that activation of neurons within the mPFC and LSN influence respiratory, metabolic and cardiac outflows in a site‐dependent manner. This study has implications with respect to the altered PFC neuronal activity seen in stress‐related and mental health disorders, and suggests how basic physiological systems may be affected.
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