Misuse and overuse of antibiotics have contributed in the last decades to a phenomenon known as antibiotic resistance which is currently considered one of the principal threats to global public ...health by the World Health Organization. The aim to find alternative drugs has been demonstrated as a real challenge. Thanks to their biodiversity, insects represent the largest class of organisms in the animal kingdom. The humoral immune response includes the production of antimicrobial peptides (AMPs) that are released into the insect hemolymph after microbial infection. In this review, we have focused on insect immune responses, particularly on AMP characteristics, their mechanism of action and applications, especially in the biomedical field. Furthermore, we discuss the Toll, Imd, and JAK-STAT pathways that activate genes encoding for the expression of AMPs. Moreover, we focused on strategies to improve insect peptides stability against proteolytic susceptibility such as D-amino acid substitutions, N-terminus modification, cyclization and dimerization.
SW480 and SW620 colon carcinoma cell lines derive from primary tumour and lymph-node metastasis of the same patient, respectively. For this reason, these cells represent an ideal system to analyse ...phenotypic variations associated with the metastatic process. In this study we analysed SW480 and SW620 cytoskeleton remodelling by measuring the cells' mechanics and morphological properties using different microscopic techniques. We observed that different specialized functions of cells, i.e. the capacity to metastasize of elongated cells inside the primary tumour and the ability to intravasate and resist shear forces of the stream of cells derived from lymph node metastasis, are reflected in their mechanical properties. We demonstrated that, together with stiffness and adhesion between the AFM tip and the cell surface, cell shape, actin organization and surface roughness are strictly related and are finely modulated by colorectal cancer cells to better accomplish their specific tasks in cancer growth and invasion.
Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase (GCase; GBA) gene. The hallmark of GD is the presence of lipid-laden Gaucher macrophages, ...which infiltrate bone marrow and other organs. These pathological macrophages are believed to be the sources of elevated levels of inflammatory mediators present in the serum of GD patients. The alteration in the immune environment caused by GD is believed to play a role in the increased risk of developing multiple myeloma and other malignancies in GD patients. To determine directly whether Gaucher macrophages are abnormally activated and whether their functional defects can be reversed by pharmacological intervention, we generated GD macrophages by directed differentiation of human induced pluripotent stem cells (hiPSC) derived from patients with types 1, 2, and 3 GD. GD hiPSC-derived macrophages expressed higher levels of tumor necrosis factor α, IL-6, and IL-1β than control cells, and this phenotype was exacerbated by treatment with lipopolysaccharide. In addition, GD hiPSC macrophages exhibited a striking delay in clearance of phagocytosed red blood cells, recapitulating the presence of red blood cell remnants in Gaucher macrophages from bone marrow aspirates. Incubation of GD hiPSC macrophages with recombinant GCase, or with the chaperones isofagomine and ambroxol, corrected the abnormal phenotypes of GD macrophages to an extent that reflected their known clinical efficacies. We conclude that Gaucher macrophages are the likely source of the elevated levels of inflammatory mediators in the serum of GD patients and that GD hiPSC are valuable new tools for studying disease mechanisms and drug discovery.
Background
Genetic factors might have a role for lack of therapeutic response to anti‐TNF‐alpha agents, as previously suggested in patients with rheumatoid arthritis and inflammatory bowel disease.
...Objectives
We evaluated the role of the main TNF‐alpha polymorphisms (−238G>A, −308G>A, −857C>T) in predicting the response to etanercept, an anti‐TNF‐alpha fusion protein.
Material and Methods
Genomic DNA was extracted from buccal epithelial cells in a series of 97 psoriatic patients who received etanercept for at least 3 months. Patients were classified as responders, if they achieved a PASI improvement ≥75% after 12 weeks of etanercept treatment, and non‐responders, if PASI improvement was <75%. Single‐nucleotide polymorphisms (SNPs) in TNF‐alpha gene (−238G>A, −308G>A, −857C>T) were genotyped by PCR restriction fragment length polymorphism (RFLP) assays.
Results
We found that patients heterozygous (GA) for the −238G>A polymorphism were more likely not responsive to therapy compared to the GG genotype. In fact, the GA genotype was found in 5/59 (8·5%) responders and in 14/38 (36·8%) non‐responders (P = 0·001). A significant relationship with therapy was also observed for the –308G>A polymorphisms. In fact, the GG, GA and AA genotypes were detected in 48 (81·4%), 9 (15·3%) and 2 (3·4%) of the 59 responders and in 22 (57·9%), 11 (28·9%) and 5 (13·2%) of the 38 non‐responder patients (P = 0·03). No association with therapy was observed for the −857C>T polymorphisms.
Conclusion
Our study supports the role of TNF‐alpha polymorphisms in predicting the response to anti‐TNF‐alpha agents. In particular, we found that the presence of −238G>A and −308G>A polymorphisms is associated with poor response to a 3‐month therapy with etanercept. However, our data have yet to be validated in larger cohorts.
Mounting evidence indicates a link between inflammation and cancer. However, the molecular mechanism(s) remains unclear. Indeed, although preclinical and clinical studies suggest that chronic ...inflammation can promote cancer development, the role(s) of inflammation in the process is likely very complex and far to be completely understood. Inflammation can promote all stages of tumor development through multiple mechanisms which include enhanced proliferation and resistance to apoptosis of initiated cells, induction of DNA mutations, promotion of angiogenesis, invasion and metastasis. On the other hand, components of tumor microenviroment, including tumor cells themselves, may promote an inflammatory state by producing inflammatory mediators. Moreover, while chronic inflammation might promote tumor formation, acute inflammation might well hamper the process and is indeed used therapeutically to inhibit tumor formation.
The present review briefly highlights the relationship between inflammation and tumorigenesis and discusses the possibility to develop chemoprevention and/or therapeutical approaches targeting components of the inflammatory responses.
Palladium nanoparticles have been increasingly used in catalytic processes, wastewater treatment, electronics, and biomedicine. However, recent evidence proved that these nanoparticles are able to ...induce adverse effects both in in vitro and in vivo models. Nevertheless, molecular mechanisms underlying the toxic effects are still poorly understood. Therefore, this study aimed to investigate the potential toxicological mechanisms of palladium nanoparticles assessing their effects on normal diploid rat fibroblast and lung carcinoma human epithelial cell lines. Several endpoints such as cell growth, cell cycle progression, DNA damage, induction of apoptosis, reactive oxygen species production and expression of cell cycle regulatory proteins were evaluated. Results showed that palladium nanoparticles inhibited cell growth in a dose- and time-dependent manner in both cell lines, although with a more evident action on fibroblasts. Interestingly, inhibition of cell growth was not associated with the induction of apoptosis. Cell cycle progression was arrested in the G0/G1 phase and DNA damage was evident in both cell lines even if only a slight increase in the intracellular reactive oxygen species levels was detected. These findings provide valuable insight into understanding the molecular mechanisms responsible of palladium nanoparticles toxicity whose identification is essential to define an adequate risk assessment process.
•Palladium nanoparticles inhibited cell growth of Rat-1 and A549 cell lines in a dose- and time-dependent manner;•Palladium nanoparticles caused a progressive arrest of both cell lines in G0/G1 phase of cell cycle without apoptosis;•Palladium nanoparticles were able to induce an increase in DNA single strand breaks in Rat-1 and A549 cell lines;•Exposure to palladium nanoparticles caused a slight increase in the intracellular ROS levels in both cell lines;•Palladium nanoparticles modulated important cell cycle regulatory proteins in Rat-1 and A549 cell lines.
Aim
The pathogenesis of cryptoglandular anal fistula (AF) is still under debate. Tissue inflammation could play a primary role. The pathological process of epithelial mesenchymal transition (EMT) ...might be involved but has never been investigated.
Method
In a prospective pilot study, 12 patients with an AF had a fistulectomy. The excised track was divided into proximal (intrasphincteric) and distal (extrasphincteric) parts which were subjected to standard histopathological examination. The cytokines IL‐8 and IL‐1beta were analysed as markers of inflammation, while EMT was evaluated by expression of TGF‐beta, Vimentin, Zeb‐1, Snail and E‐cadherin. The mRNA and protein expression of these molecules was investigated by real‐time PCR (RT‐PCR), Western blot analysis and immunohistochemistry and was compared with that of the normal adjacent tissue.
Results
Chronic inflammation and granulation tissue and a stratified epithelium were evident on standard histopathological examination. The cytokine IL‐8 was more expressed in the proximal than the distal part of the track (fold increase 4.34 vs 3.60), while the reverse was found for IL‐1beta (fold increase 1.33 vs 2.01); both were more intensely expressed compared with the normal anal mucosa. EMT was demonstrated, in both proximal and distal parts of the track, with an increase of TGF‐beta, Vimentin, Zeb‐1 and Snail and a mean decrease of E‐cadherin. Western blot analysis and immunohistochemistry confirmed the protein expression.
Conclusion
The study suggests that chronic inflammation is present in cryptoglandular fistulas. The inflammatory pattern might be different in the proximal than in the distal part of the fistula track. The cytokines IL‐1beta and IL‐8 could play a possible role in fistula formation. The study demonstrates for the first time the potential importance of EMT in the pathogenesis of cryptoglandular AF.
Summary
Background Dermoscopic monitoring of melanocytic lesions increases the likelihood that featureless melanomas are not overlooked and minimizes the excision of benign lesions.
Objective To ...examine clinical outcome and patient compliance using different follow‐up protocols.
Methods A retrospective analysis of 600 lesions from 405 patients (aged 6–79 years) was performed to examine patient compliance and clinical outcome in patients with multiple atypical melanocytic lesions undergoing sequential dermoscopy imaging during short‐, medium‐ or long‐term follow‐up. Based on the degree of dermoscopic atypical features, patients were scheduled for short‐term monitoring with follow‐up after 3 months, medium‐term monitoring with follow‐up after 6 months or long‐term monitoring with annual follow‐up. Criteria leading to excision of monitored lesions differed according to the follow‐up protocol.
Results In a median follow‐up period of 23 months, 54 (9%) lesions were excised, revealing 12 early melanomas (occurring in 3% of monitored patients), one basal cell carcinoma and 41 melanocytic naevi. The melanoma/benign ratio of excised lesions was 1 : 3·4. Seven of 12 melanomas showed changes after two to four visits, corresponding to 8–54 months of follow‐up. Patient compliance was 84% for short‐term monitoring, 63% for medium‐term monitoring and 30% for long‐term monitoring.
Conclusions In patients with multiple naevi sequential dermoscopy imaging is a useful strategy to avoid missing melanomas while minimizing unnecessary excision of benign lesions. For better compliance, the first re‐examination should be scheduled at 3 months after the baseline visit. Regular annual follow‐up monitoring is also needed to detect slow‐growing melanomas in which subtle changes may become apparent only over time.
The widespread industrial application of nanomaterials (NMs) has dramatically increased the likelihood of environmental and occupational exposure of humans to such xenobiotics. This issue, together ...with the increasing public health interest in understanding the effects of chemicals on endocrine system, encouraged to investigate the disruptive potential of NMs on the endocrine function. Therefore, the aim of this study was to evaluate the effects of palladium nanoparticles (Pd-NPs) on the female reproductive system of Wistar rats, intravenously exposed to different doses (0.12, 1.2, and 12 µg/kg), through the assessment of possible quantitative changes in the serum concentrations of several sex hormones. Our results demonstrated that the highest exposure doses significantly reduced the estradiol and testosterone concentrations, while increased the luteinizing hormone levels in treated animals compared to controls. Such alterations are indicative for an abnormal reproductive axis function. However, further investigations are needed to clarify the role of the different NP physicochemical properties in determining such effects, and possible underlining molecular mechanisms, as well as their relevance for the development of diseases in the female reproductive system. Overall, this may be helpful to define accurate risk assessment and management strategies to protect the health of the general and occupational populations exposed to Pd-NPs.
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