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Endothelial dysfunction with subsequent degeneration and vasoocclusive remodeling is the hallmark of many cardiovascular disorders including pulmonary vascular disease (PVD). To date, the available treatments slows disease progression but does not prevent deterioration. Reversing such pathologies would spare many patients risky surgeries and long waiting lists for a possible organ donor. Peroxisome proliferator-activated receptor agonists were first introduced as sole insulin sensitizers, however, there is increasing body of evidence that they have different actions on DNA which might help reverse vascular degeneration. This effect appears to be mainly achieved through enhancement of DNA damage responses (DDR). The aforementioned effect could offer new insights about repurposing drugs for achieving organ or tissue regeneration, an understudied field named drug-induced regenerative medicine.

Background: With the current mass international roll out of several vaccines against SARS-Cov-2, several reports of unheeded complications have made headlines. One of which involves myocarditis with the now FDA fully approved vaccine, Pfizer, and others. We hypothesize through this study that a dysregulated micro-RNA response resulting from such type of vaccines can be involved in triggering myocarditis. Methodology: Embase, Medline and the Cochrane Central Register were used to search for specific keywords such as “mRNA COVID-19 vaccines” AND “Myocarditis” for relevant publications up to 1st of September 2021. The systematic review was performed using PRISMA protocolResults:Literature review has identified 26 cases series and reports involving the development of myocarditis from mRNA vaccines, a total of 89 patients were included. Age range was clearly identified in 66 patients. Among those 66 patients, 94% were below 50 years of age, also out of 89 patients, 94% were males. Myocarditis developed, after a median time of 72 hours of the 2nd dose. 90 of cases of myocarditis developed myocarditis after the 2nd dose, the few patients developing myocarditis after the first dose were either predisposed by a history of myocarditis or a history of previous COVID-19 infection. Conclusion:In conclusion, interpretation of the results in view of the suggested hypothesis, reveals that the micro-RNAs implicated in myocarditis in general are as well implicated in the pathogenesis of severe COVID-19, this can explain why patients having a first dose with a history of COVID-19 can develop myocarditis from mRNA vaccines, also the relatively higher likelihood of this complication in males and younger aged individuals can be explained by the upregulation of key myocarditis related miRNAs in those two strata, due to higher muscle mass and suggests performing a sarcopenia index in recipients of the vaccine to correlate it with the likelihood of this complication. This could later set a cut-off of this easy bed-side index to stratify cases a higher risk of this rare complication.

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.

C-type lectin receptors (CLRs) play key roles in antifungal defense. CLR-induced NF-κB is central to CLR functions in immunity, and thus, molecules that control the amplitude of CLR-induced NF-κB could profoundly influence host defense against fungal pathogens. However, little is known about the mechanisms that negatively regulate CLR-induced NF-κB, and molecules which act on the CLR family broadly and which directly regulate acute CLR-signaling cascades remain unidentified. Here, we identify the ubiquitin-editing enzyme A20 as a negative regulator of acute NF-κB activation downstream of multiple CLR pathways. Absence of A20 suppression results in exaggerated CLR responses in cells which are A20 deficient and also cells which are A20 haplosufficient, including multiple primary immune cells. Loss of a single allele of A20 results in enhanced defense against systemic Candida albicans infection and prolonged host survival. Thus, A20 restricts CLR-induced innate immune responses in vivo and is a suppressor of host defense against systemic fungal infection.

Furin, a cleavage enzyme, is increasingly recognized in the pathogenesis of metabolic syndrome. Its cleavage action is an essential activation step for the endothelial pathogenicity of several viruses including SARS-CoV-2. This Furin-mediated endothelial tropism seems to underlie the multi-organ system involvement of COVID-19; which is a feature that was not recognized in the older versions of coronaviridae. Obese and diabetic patients, males, and the elderly, have increased serum levels of Furin, with its increased cellular activity; this might explain why these subgroups are at an increased risk of COVID-19 related complications and deaths. In contrast, smoking decreases cellular levels of Furin, this finding may be at the origin of the decreased severity of COVID-19 in smokers. Chinese herbal derived luteolin is suggested to be putative Furin inhibitor, with previous success against Dengue Fever. Additionally, Furin intracellular levels are largely dependent on concentration of intracellular ions, notably sodium, potassium, and magnesium. Consequently, the use of ion channel inhibitors, such as Calcium Channel blockers or Potassium Channel blockers, can prevent cellular transfection early in the course of the illness. Nicotine patches and Colchicine have also been suggested as potential therapies due to Furin mediated inhibition of COVID-19., Highlights • 1-SARS-CoV-2 harbors a polybasic cleavage site. • 2-This polybasic cleavage site leads to its canonical activation by a cellular enzyme termed Furin. • 3-Furin is highly expressed in Endothelial, leading to endothelitis and vascular inflammation in COVID-19. • 4-This also explains the augmented manifestations of COVID-19 in Obese and Diabetic patients. • 5-The use of Chinese herbals and ion channel inhibitors can block the endothelial penetration of SARS-CoV-2.

IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity. IRGM dysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction., Author summary Intestinal macrophages are seeded by peripheral monocytes that enter the intestine and mature into an essential component of immune defense. While this process is shaped by intestinal bacteria, the mechanisms that regulate the process, and their roles in host defense to enteric pathogens are poorly defined. We find that Irgm1 –the orthologue of the human Crohn’s disease resistance gene, IRGM–is required for monocyte/macrophage remodeling in response to the gram-negative enteric pathogen Citrobacter rodentium, with absence of Irgm1 leading to systemic spread of the bacterium and host mortality. Failure to remodel colonic monocytes/macrophages was due to a key requirement for Irgm1 in colon-infiltrating monocytes, which underwent dramatically high rates of cell death, specifically during the setting of enteric bacterial infection. While Irgm1/IRGM proteins are well appreciated for their role in regulating intracellular bacterial killing, our results expand the paradigm for Irgm1/IRGM-mediated host defense by demonstrating an essential function for Irgm1/IRGM to control the survival and population remodeling of monocytes and macrophages that expand during enteric infection and defend against pathogenic bacteria. These findings have significant implications for the genesis of Crohn’s disease in individuals that carry IRGM variants.

Coronavirus disease 2019 (COVID-19) is a serious illness that has rapidly spread throughout the globe. The seriousness of complications puts significant pressures on hospital resources, especially the availability of ICU and ventilators. Current evidence suggests that COVID-19 pathogenesis majorly involves microvascular injury induced by hypercytokinemia, namely interleukin 6 (IL-6). We recount the suggested inflammatory pathway for COVID-19 and its effects on various organ systems, including respiratory, cardiac, hematologic, reproductive, and nervous organ systems, as well examine the role of hypercytokinemia in the at-risk geriatric and obesity subgroups with upregulated cytokines' profile. In view of these findings, we strongly encourage the conduction of prospective studies to determine the baseline levels of IL-6 in infected patients, which can predict a negative outcome in COVID-19 cases, with subsequent early administration of IL-6 inhibitors, to decrease the need for ICU admission and the pressure on healthcare systems. Video abstract: http://links.lww.com/CAEN/A24.

Coronavirus disease 2019 (COVID-19) has been declared a pandemic on 11 March 2020 by the WHO. Despite being mainly a respiratory virus, cardiac complications have been described. These range from sudden cardiac death to subtle diastolic dysfunction after recovery from COVID-19. The commonest cardiac presentation to date is acute heart failure resulting from biventricular or left ventricular hypokinesis and elevation of cardiac troponins. It has been shown that COVID-19 downregulates angiotensin-converting enzyme-2, which has protective effects on the endothelium and cardiomyocytes. It has also been proven that COVID-19 induces a state of hypercytokinaemia, some cytokines such as interleukin-1 and interleukin-6 have an injurious effect on the myocardium and endothelium, respectively. Such pathogenic mechanisms might play a crucial role in induction of cardiomyocyte injury and impaired myocardial perfusion probably through coronary endothelial dysfunction. The understanding and linking of such mechanisms might help in tailoring drug repurposing for treatment or prophylaxis of COVID-19 cardiovascular complications.

IRGMand its mouse orthologueIrgm1are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity.IRGMdysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility toCitrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to controlC. rodentiumoutgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing ofC. rodentiumor exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response toC. rodentiuminfection and are essential forC. rodentiumimmunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced byC. rodentiuminfection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.Author SummaryIntestinal macrophages are seeded by peripheral monocytes that enter the intestine and mature into an essential component of immune defense. While this process is shaped by intestinal bacteria, the mechanisms that regulate the process, and their roles in host defense to enteric pathogens are poorly defined. We find thatIrgm1– the orthologue of the human Crohn’s disease resistance gene,IRGM– is required for monocyte/macrophage remodeling in response to the gram-negative enteric pathogenCitrobacter rodentium, with absence of Irgm1 leading to systemic spread of the bacterium and host mortality. Failure to remodel colonic monocytes/macrophages was due to a key requirement for Irgm1 in colon-infiltrating monocytes, which underwent dramatically high rates of cell death, specifically during the setting of enteric bacterial infection. While Irgm1/IRGM proteins are well appreciated for their role in regulating intracellular bacterial killing, our results expand the paradigm for Irgm1/IRGM-mediated host defense by demonstrating an essential function for Irgm1/IRGM to control the survival and population remodeling of monocytes and macrophages that expand during enteric infection and defend against pathogenic bacteria. These findings have significant implications for the genesis of Crohn’s disease in individuals that carryIRGMvariants.

COVID-19 has shown a substantial variation in the rate and severity by which it impacts different demographic groups. Specifically, it has shown a predilection towards obese patients as well as as well as other vulnerable groups including predilection of males over females, old age over young age and black races over Caucasian ones.. Single cell sequencing studies have highlighted the role of cell polarity and the co-expression of proteases, such as Furin, along with ACE2 in the genesis of coronavirus disease rather than exclusively link tissue involvement with ACE2 levels thought previously. It has also forged a connection between the genetic and immune cellular mechanisms underlying COVID infection and the inflammatory state of obese patients, offering a more accurate explanation as to why obese patients are at increased risk of poor COVID outcomes. These commonalities encompass macrophage phenotype switching, genetic expression switching, and overexpression of the pro-inflammatory cytokines, depletion of the regulatory cytokines, in situ T cell proliferation, and T cell exhaustion. These findings demonstrate the necessity of single cell sequencing as a rapid means to identify and treat those who are most likely to need hospital admission and intensive care, in the hopes of precision medicine. Furthermore, this study underlines the use of immune modulators such as Leptin sensitizers, rather than immune suppressors as anti-inflammation therapies to switch the inflammatory response from a drastic immunological type 1 response to a beneficial type 2 effective one., Highlights • ScRNA-seq focuses on the analysis of individual cells, instead of bulk cell populations, and can lead to a more insightful characterization of local microenvironments. • ScRNA-seq unleashed that tissue tropism in COVID-19 is not solely determinant by ACE2 distribution but rather by Furin. • ScRNA-seq in COVID-19 revealed two distinct types of immunologic reactions, deleterious type 1 characterized by inefficient antigen presentation, decreased memory B cells, imbalance between M1 and M2 macrophages and T cell exhaustion, and beneficial type 2 reaction which exactly the reverse of the type 1. • The immunotype 1 reaction is intriguingly similar to the immune landscape seen in obese individuals when leptin resistance sets in. • This might indicate that the use of leptin sensitizers to induce an immunologic switch from immunotype 1 to immunotype 2 can greatly improve the outcome of COVID-19 cases. • ScRNA-seq was also able to unveil the disparity between aggressive and milder strains of SARS-CoV-2, which are mainly related to their affinity to cellular activation by Furin. • The applications of ScRNA-seq may help to anticipate cases at higher risk of severe COVID-19 at their earliest encounter.

Introduction There is an increased body of evidence that Obstructive Sleep apnea (OSA) in obese patients has familial tendencies. This familial predilection might be mediated through tendencies to atopy with subsequent nasal obstruction, tendencies to adenotonsillar enlargement by fat deposition, or through differential fatty deposits in the airway. The aim of this study was to study if paternal or maternal OSA might be predictive of OSA in offspring and to determine the relationship of OSA to Body Mass Index (BMI), gender, and waist circumference (WC). Methods 100 obese patients retrieved from a consortium of Egyptian Schools were screened and their parents using sleep apnea clinical score (SACS), their gender, BMI, and WC were noted. For the performance of Receiver Operating Characteristic study, obese children were divided according to their SACS into high risk (1) (SACS>75) and low risk (0) (SACS≤75). The sensitivity of each of BMI, WC, gender, paternal and maternal SACS as predictors of OSA high risk was determined. Results: Paternal OSA risk was the single significant predictor of OSA risk in obese children (Sensitivity: 89%, Specificity: 97%), WC was the second-best predictor (Sensitivity: 78%, Specificity: 89%), female offsprings were at higher risk to be involved, BMI was a weak predictor of OSA risk with a cut off>34. Finally, yet importantly, maternal OSA risk was unrelated to OSA risk in obese children. Conclusion This study confirms that genetic factors might play a much more important role than the degree of obesity in determining OSA risk in obese patients, these findings open the door to more in-depth studies to understand the genetic mechanisms involved in such a relationship.

Immune responses in the intestine are coordinated by specialized populations of mononuclear phagocytes. Although the functions of intestine-resident mononuclear phagocytes and the different cell subsets that constitute these populations are thought uniform across the entire intestine, it is clear that the anatomy, microbes, and immunological demands are distinct for small and large intestine. Whether these distinctions also include organ-specific mononuclear phagocyte populations, or that these have organ-specific roles in immunity are unknown. Here we identify two novel subsets of colon-specific mononuclear phagocytes, a dendritic cell (DC) subset and a macrophage subset, both of which are exclusive to the colon and are not found in small intestine. These colon-specific DCs and macrophages co-expressed CD14 and CD24, markers which are generally singularly expressed by intestinal DCs and macrophages and commonly used to distinguish between these two cell types. Colon-specific CD14+CD24+ DCs and macrophages failed to express macrophage markers CX3CR1, F4/80, CD64 and CD88, and surprisingly, both the DC and macrophage subset were dependent on the transcription factor IRF4. We further find that colon and small intestine have distinct antigen presenting cell (APC) requirements for Th17 immunity and that while colon-specific CD14+CD24+ APCs were essential for Th17 immunity in the colon, this role in small intestine was mediated by different APC subsets. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.