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Melanin is a dark color pigment biosynthesized naturally in most living organisms. Fungal melanin is a major putative virulence factor of Mucorales fungi that allows intracellular persistence by inducing phagosome maturation arrest. Recently, it has been shown that the black pigments of Rhizopus delemar is of eumelanin type, that requires the involvement of tyrosinase (a copper-dependent enzyme) in its biosynthesis. Herein, we have developed a series of compounds (UOSC-1-14) to selectively target Rhizopus melanin and explored this mechanism therapeutically. The compounds were designed based on the scaffold of the natural product, cuminaldehyde, identified from plant sources and has been shown to develop non-selective inhibition of melanin production. While all synthesized compounds showed significant inhibition of Rhizopus melanin production and limited toxicity to mammalian cells, only four compounds (UOSC-1, 2, 13, and 14) were selected as promising candidates based on their selective inhibition to fungal melanin. The activity of compound UOSC-2 was comparable to the positive control kojic acid. The selected candidates showed significant inhibition of Rhizopus melanin but not human melanin by targeting the fungal tyrosinase, and with an IC50 that are 9 times lower than the reference standard, kojic acid. Furthermore, the produced white spores were phagocytized easily and cleared faster from the lungs of infected immunocompetent mice and from the human macrophages when compared with wild-type spores. Collectively, the results suggested that the newly designed derivatives, particularly UOSC-2 can serve as promising candidate to overcome persistence mechanisms of fungal melanin production and hence make them accessible to host defenses.

The performance of apparently biocompatible implanted bovine bone grafts may be compromised by unresolved chronic inflammation, and poor graft incorporation leading to implant failure. Monitoring the intensity and duration of the inflammatory response caused by implanted bone grafts is crucial. In this study, the ability of demineralized (DMB) and decellularized (DCC) bovine bone substitutes in initiating inflammatory responses to peripheral blood monocyte-derived macrophages (PBMMs) was investigated. The response of PBMMs to bone substitutes was evaluated by using both direct and indirect cell culture, reactive oxygen species (ROS) generation, apoptosis, immunophenotyping, and cytokine production. Analysis of DMB and DCC substitutes using scanning electron microscope (SEM) showed a roughened surface with a size ranging between 500 and 750 μm. PBMMs treated with DMB demonstrated cell aggregation and clumping mimicking lipopolysaccharide (LPS) treated PBMMs and a higher proliferation ability (166.93%) compared to control (100%) and DCC treatments (115.64%; p<0.001) at 24h. This was associated with a significantly increased production of intracellular ROS in PBMMs exposed to DMB substitutes than control (3158.5 vs 1715.5; p<0.001) and DCC treatment (2117.5). The bone substitute exposure also caused an increase in percentage apoptosis which was significantly (p<0.0001) higher in both DMB (27.85) and DCC (29.2) treatment than control (19.383). A significant increase in proinflammatory cytokine expression (TNF-α: 3.4 folds; p<0.05) was observed in DMB substitute-treated PBMMs compared to control. Notably, IL-1β mRNA was significantly higher in DMB (21.75 folds; p<0.0001) than control and DCC (5.01 folds). In contrast, DCC substitutes exhibited immunoregulatory effects on PBMMs, as indicated by the expression for CD86, CD206, and HLDR surface markers mimicking IL-4 treatments. In conclusion, DMB excites a higher immunological response compared to DCC suggesting decellularization process of tissues dampen down inflammatory reactions when exposed to PBMM. [ABSTRACT FROM AUTHOR]

Background: The safety of deferred stenting as a technique in patients with ST segment elevation myocardial infarction (STEMI) is debatable by guidelines. This study aims to see how effective immediate stenting versus delayed stenting in lowering angiographic outcomes (no/slow reflow, distal embolization, and improved myocardial blush grade MBG) in STEMI patients. Methods: Multi centers prospective clinical trial included 108 patients with STEMI with heavy thrombus burden. Patients were divided equally into two groups: Group (1): which included 54 patients who underwent immediate stenting and Group (2) which involved 54 patients who underwent deferred stenting. Procedural angiographic events were the primary endpoints, while the secondary endpoints were the presence of Major Adverse Cardiac Events (MACE) and bleeding complications with follow up duration for 6 months. Results: Deferred stenting patients had a statistically significant decrease in slow flow and no reflow (P = 0.03). In addition, the defer group showed a greater increase in myocardial blush grade (MBG) than immediate stenting group (P value 0.04). Distal embolization, on the other hand, showed no statistical difference (P value 0.1), and there was no statistically significant difference between the two groups in terms of bleeding complications (P value 0.7), however there was no statistically meaningful improvement in the deferred stenting group (P value = 0.3) regarding the composite of MACEs between the two groups. Conclusions: Deferred stenting was associated with improved immediate myocardial perfusion, less no/slow reflow, but not with a substantial decrease in MACEs at six months, as a result, direct stenting is a standard treatment option for STEMI patients. [ABSTRACT FROM AUTHOR]

Background: In patients with symptomatic Heart Failure (HF) and wide QRS duration, cardiac resynchronization therapy (CRT) causes reduction of morbidity and mortality. However, it's unclear which patient features predict short-term response to this device therapy. The research aimed to study which cases characteristics could expect short-term clinical and echocardiographic response to CRT. Methods: This prospective cohort study involved 40 patients indicated for CRT device. The study was conducted in the cardiology departments, faculty of medicine, Zagazig University, and Police hospital at the period from October 2018 to October 2020. Clinical, laboratory, electrocardiographic, and echocardiographic assessments were performed pre and six months after implantation. Results: Forty patients undergoing CRT implantation were included among which, 30 (75%) patients were considered responders after six months. From the present study, the responders to CRT were more frequently to be females with younger age than non -responders. Nonischemic HF, left bundle branch block (LBBB) morphology and New York Heart Association (NYHA) functional class III were significantly more frequent in responders. Furthermore, responders had significantly wider baseline QRS duration, smaller baseline LV diastolic and systolic dimension and volumes, greater ejection fraction, lower levels of brain natriuretic peptide (BNP), and more baseline intra-ventricular dyssynchrony. Conclusions: We concluded that pre-implantation independent Predictors of good CRT response are LBBB morphology, septal to posterior wall mechanical delay, wide QRS duration, interventricular mechanical delay, NYHA functional class III, and lower levels of BNP. Large scale study is recommended for further verification of study results. [ABSTRACT FROM AUTHOR]

Background: Secundum atrial septal defects (ASDs) are the most common congenital heart diseases and its closure affords changes in the function of the pulmonary activities. Our study aimed to demonstrate that the closure ASD not only improves cardiac function but also results in symptomatic relief by improving functional class by improving exercise tolerance and pulmonary functions. Methods: This is a prospective study was conducted on 100 patients underwent device closure of secundum ASD. Investigations included NT-pro-brain natriuretic peptide levels (NT-pro-BNP), electrocardiography, chest X-ray, transthoracic echocardiogram, spirometry, and 6-min walk test, before and 3 months after the procedure. Results: All patients were classified according to significant symptomatic improvement into group I (not improved) and group II (improved). Regards NYHA classification, pulmonary hypertension, tricuspid regurgitation and NTpro-BNP, there was statistically significant lower values both pre-closure and postclosure in the improved group (p<0.001). There was statistical significant difference in pulmonary functions (spirometry and 6-minute walk test) in ASD patients before and 3 months after ASD closure in both groups as all parameters (FEF 25-75, FVC, and FEV1 and 6-minute walk test) as they were statistically significant higher values in the improved group both pre-closure and post-closure. The significant predictors was age < 48, ASD size ≤35, pulmonary hypertension (mild/moderate), FEF 75-25 ≥61, FVC≥67, FEV 1%≥64 and 6-MWTD ≥325 Conclusion: Transcatheter ASD device closure leads to significant improvement in the heart dimensions especially right-sided dimensions and functional class by improving exercise tolerance and pulmonary functions. [ABSTRACT FROM AUTHOR]

In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity., Introduction Since the work of Sheri and that of Murphy and Sturm (1), the prevailing paradigm has been that the inert immunological status of the CNS parenchyma is maintained by [...]

Aims: Lipopolysaccharides (LPS)‐activated human dental pulp stem cells (hDPSCs) and macrophage co‐cultures showed downregulated TNF‐α secretion that is modulated by hDPSCs through IDO axis, whereas the secretory levels of IL‐1β remained unchanged. Therefore, sustained production of IL‐1β could contribute to progressive dental pulp inflammation. However, the role of interleukin‐1 receptor antagonist (IL‐1RA) in downregulating the secretion of IL‐1β and TNF‐α in LPS‐activated M0/M1/M2 macrophage and hDPSCs co‐culture has not been studied yet. Therefore, the aim of the present study was to determine the immunomodulatory role of blocking IL‐1 receptors in DPSCs macrophage co‐culture activated with LPS. Methodology: Human monocytic cell line THP‐1 was polarized to M0, M1 and M2 macrophages and co‐cultured with hDPSCs. The viability of the co‐cultured cells was assessed by apoptosis assay. Co‐cultures were activated with LPS followed by the assessment of gene expression and protein levels of IL‐1β and TNF‐α with and without IL‐1RA blocking via qRT‐PCR and cytokine flex assay by flow cytometry. Data from three separate experiments were analysed using one‐way anova followed by Tukey's post hoc test and a p‐value of <.05 was considered statistically significant. Results: THP‐1‐derived M0, M1 and M2 macrophages co‐cultured with hDPSCs showed spindle and round‐shaped cells, with >90% viability when assessed by apoptosis assay. Inflammatory TNF‐α and IL‐1β profiles in stimulated co‐cultures showed upregulated IL‐1β, whereas TNF‐α was downregulated (p <.05). Anti‐inflammatory gene expression levels of IL‐10 and TGF‐β were downregulated (p <.05). Blocking with IL‐1RA resulted in a remarkable decrease in IL‐1β at the gene expression and protein production levels whilst TNF‐α levels remained low (p <.05). Levels of anti‐inflammatory cytokine IL‐10 showed no significant difference. Conclusion: Blocking the IL‐1 receptor in hDPSCs and macrophage (M0, M1, M2) co‐cultures activated with LPS resulted in downregulation of inflammatory cytokines IL‐1β and TNF‐α. These findings highlight the immunomodulatory effect of IL‐1RA in inflammatory conditions of dental pulp infections. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a devastating neurological disease that predominantly affects young adults resulting in severe personal and economic impact. The majority of therapies for this disease were developed in, or are beneficial in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. While known to target adaptive anti-CNS immune responses, they also target, the innate immune arm. This mini-review focuses on the role of dendritic cells (DCs), the professional antigen presenting cells of the innate immune system. The evidence for a role for DCs in the appropriate regulation of anti-CNS autoimmune responses and their role in MS disease susceptibility and possible therapeutic utility are discussed. Additionally, the current controversy regarding the evidence for the presence of functional DCs in the normal CNS is reviewed. Furthermore, the role of CNS DCs and potential routes of their intercourse between the CNS and cervical lymph nodes are considered. Finally, the future role that this nexus between the CNS and the cervical lymph nodes might play in site directed molecular and cellular therapy for MS is outlined. [ABSTRACT FROM AUTHOR]

CCAAT enhancer binding protein-delta (C/EBPδ) is a transcription factor that regulates inflammatory processes mediating bystander neuronal injury and CNS autoimmune inflammatory disease. The mechanism of the involvement of C/EBPδ in these processes remains to be determined. Here, we examined the cellular source(s) and mechanisms by which C/EBPδ may be involved in an animal model of multiple sclerosis. Mice deficient in C/EBPδ expression exhibited less severe clinical disease than wild-type littermates in response to induction of experimental autoimmune encephalomyelitis (EAE) by vaccination with a myelin oligodendrocyte glycoprotein (MOG) fragment. This reduction in EAE severity was associated with a significant alteration in the complement of major CNS T-helper (Th) cell subtypes throughout disease, manifest as reduced ratios of Th17 cells to regulatory T-cells (Tregs). Studies in bone marrow chimeric mice indicated that C/EBPδ expression by peripherally derived immune cells mediates C/EBPδ involvement in EAE. Follow up in vitro and in vivo examination of dendritic cell (DC) mediated Th-cell development suggests that C/EBPδ suppresses DC expression of interleukin-10 (IL-10), favoring Th17 over Treg development. In vitro and in vivo blockade of IL-10 signaling attenuated the effect of reduced C/EBPδ expression by DCs on Th17:Treg ratios. These findings identify C/EBPδ as an important DC transcription factor in CNS autoimmune inflammatory disease by virtue of its capacity to alter the Th17:Treg balance in an IL-10 dependent fashion. [ABSTRACT FROM AUTHOR]

Candida auris has drawn global attention due to its alarming multidrug resistance and the emergence of pan resistant strains. C. auris poses a significant risk in nosocomial candidemia especially among immunocompromised patients. C. auris showed unique virulence characteristics associated with cell wall including cell polymorphism, adaptation, endurance on inanimate surfaces, tolerance to external conditions, and immune evasion. Notably, it possesses a distinctive cell wall composition, with an outer mannan layer shielding the inner 1,3-β glucan from immune recognition, thereby enabling immune evasion and drug resistance. This review aimed to comprehend the association between unique characteristics of C. auris's cell wall and virulence, resistance mechanisms, and immune evasion. This is particularly relevant since the fungal cell wall has no human homology, providing a potential therapeutic target. Understanding the complex interactions between the cell wall and the host immune system is essential for devising effective treatment strategies, such as the use of repurposed medications, novel therapeutic agents, and immunotherapy like monoclonal antibodies. This therapeutic targeting strategy of C. auris holds promise for effective eradication of this resilient pathogen., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Multiple sclerosis (MS) is a devastating neurological disease that predominantly affects young adults resulting in severe personal and economic impact. The majority of therapies for this disease were developed in, or are beneficial in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. While known to target adaptive anti-CNS immune responses, they also target, the innate immune arm. This mini-review focuses on the role of dendritic cells (DCs), the professional antigen presenting cells of the innate immune system. The evidence for a role for DCs in the appropriate regulation of anti-CNS autoimmune responses and their role in MS disease susceptibility and possible therapeutic utility are discussed. Additionally, the current controversy regarding the evidence for the presence of functional DCs in the normal CNS is reviewed. Furthermore, the role of CNS DCs and potential routes of their intercourse between the CNS and cervical lymph nodes are considered. Finally, the future role that this nexus between the CNS and the cervical lymph nodes might play in site directed molecular and cellular therapy for MS is outlined.