Inflammation: The Cause of All Diseases

Autoimmune hepatitis (AIH) is an inflammatory liver disease wherein the body’s immune system instigates an attack on the liver, causing inflammation and hepatic impairment. This disease usually manifests in genetically predisposed individuals and is triggered by stimuli or environments such as viral infections, environmental toxins, and drugs. The causal role of COVID-19 vaccination in AIH remains uncertain. This review of 39 cases of vaccine-related AIH indicates that female patients above the age of 50 years or those with potential AIH risk factors may be susceptible to vaccine-related AIH, and the clinical features of vaccine-associated AIH are similar to those of idiopathic AIH. These features commonly manifest in patients after the first dose of vaccination, with symptom onset typically delayed by 10–14 days. The incidence of underlying liver disease in patients with potential health conditions associated to liver disease is similar to that of patients without preexisting illnesses. Steroid administration is effective in treating vaccine-related AIH-susceptible patients, with most patients experiencing improvement in their clinical symptoms. However, care should be taken to prevent bacterial infections during drug administration. Furthermore, the possible pathogenic mechanisms of vaccine-associated AIH are discussed to offer potential ideas for vaccine development and enhancement. Although the incidence of vaccine-related AIH is rare, individuals should not be deterred from receiving the COVID-19 vaccine, as the benefits of vaccination significantly outweigh the risks. Full article

: Although early recognition of sepsis is essential for timely treatment and can improve sepsis outcomes, no marker has demonstrated sufficient discriminatory power to diagnose sepsis. This study aimed to compare gene expression profiles between patients with sepsis and healthy volunteers to determine the accuracy of these profiles in diagnosing sepsis and to predict sepsis outcomes by combining bioinformatics data with molecular experiments and clinical information. We identified 422 differentially expressed genes (DEGs) between the sepsis and control groups, of which 93 immune-related DEGs were considered for further studies due to immune-related pathways being the most highly enriched. Key genes upregulated during sepsis, including S100A8, S100A9, and CR1, are responsible for cell cycle regulation and immune responses. Key downregulated genes, including CD79A, HLA-DQB2, PLD4, and CCR7, are responsible for immune responses. Furthermore, the key upregulated genes showed excellent to fair accuracy in diagnosing sepsis (area under the curve 0.747–0.931) and predicting in-hospital mortality (0.863–0.966) of patients with sepsis. In contrast, the key downregulated genes showed excellent accuracy in predicting mortality of patients with sepsis (0.918–0.961) but failed to effectively diagnosis sepsis. In conclusion, bioinformatics analysis identified key genes that may serve as biomarkers for diagnosing sepsis and predicting outcomes among patients with sepsis. Full article

Scurvy is a nutritional deficiency caused by low vitamin C levels that has been described since ancient times. It leads to a varied presentation, affecting multiple organ systems due to its role in the biochemical reactions of connective tissue synthesis. Common manifestations include gingival bleeding, arthralgias, skin discoloration, impaired wound healing, perifollicular hemorrhage, and ecchymoses. Although there has been a dramatic reduction in the prevalence of scurvy in modern times owing to vitamin C supplementation and intake, sporadic cases still occur. In developed countries, it is mainly diagnosed in the elderly and malnourished individuals and is associated with alcoholism, low socio-economic status, and poor dietary habits. Scurvy has been an unusual cause of gastrointestinal (GI) bleeding among other GI manifestations. It can be adequately treated and prevented via vitamin C supplementation. Full article

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and the central neurons system. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies have improved life expectancy; however, this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, better assessment of dystrophic heart and brain pathophysiology is needed. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration; however, neuroinflammation’s role is largely unknown in DMD despite being prevalent in other neurodegenerative diseases. Here, we present an inflammatory marker translocator protein (TSPO) positron emission tomography (PET) protocol for in vivo concomitant assessment of immune cell response in hearts and brains of a dystrophin-deficient mouse model [mdx:utrn(+/−)]. Preliminary analysis of whole-body PET imaging using the TSPO radiotracer, [¹⁸F]FEPPA in four mdx:utrn(+/−) and six wildtype mice are presented with ex vivo TSPO-immunofluorescence tissue staining. The mdx:utrn(+/−) mice showed significant elevations in heart and brain [¹⁸F]FEPPA activity, which correlated with increased ex vivo fluorescence intensity, highlighting the potential of TSPO-PET to simultaneously assess presence of cardiac and neuroinflammation in dystrophic heart and brain, as well as in several organs within a DMD model. Full article

IL(Interleukin)-4 is the main macrophage M2-type activator and induces an anti-inflammatory phenotype called alternative activation. The IL-4 signaling pathway involves the activation of STAT (Signal Transducer and Activator of Transcription)-6 and members of the MAPK (Mitogen-activated protein kinase) family. In primary-bone-marrow-derived macrophages, we observed a strong activation of JNK (Jun N-terminal kinase)-1 at early time points of IL-4 stimulation. Using selective inhibitors and a knockout model, we explored the contribution of JNK-1 activation to macrophages’ response to IL-4. Our findings indicate that JNK-1 regulates the IL-4-mediated expression of genes typically involved in alternative activation, such as Arginase 1 or Mannose receptor, but not others, such as SOCS (suppressor of cytokine signaling) 1 or p21^Waf−1 (cyclin dependent kinase inhibitor 1A). Interestingly, we have observed that after macrophages are stimulated with IL-4, JNK-1 has the capacity to phosphorylate STAT-6 on serine but not on tyrosine. Chromatin immunoprecipitation assays revealed that functional JNK-1 is required for the recruitment of co-activators such as CBP (CREB-binding protein)/p300 on the promoter of Arginase 1 but not on p21^Waf−1. Taken together, these data demonstrate the critical role of STAT-6 serine phosphorylation by JNK-1 in distinct macrophage responses to IL-4. Full article

The COVID-19 pandemic was triggered by the coronavirus SARS-CoV-2, whose peak occurred in the years 2020 and 2021. The main target of this virus is the lung, and the infection is associated with an accentuated inflammatory process involving mainly the innate arm of the immune system. Here, we described the induction of a pulmonary inflammatory process triggered by the intranasal (IN) instillation of UV-inactivated SARS-CoV-2 in C57BL/6 female mice, and then the evaluation of the ability of vitamin D (VitD) to control this process. The assays used to estimate the severity of lung involvement included the total and differential number of cells in the bronchoalveolar lavage fluid (BALF), histopathological analysis, quantification of T cell subsets, and inflammatory mediators by RT-PCR, cytokine quantification in lung homogenates, and flow cytometric analysis of cells recovered from lung parenchyma. The IN instillation of inactivated SARS-CoV-2 triggered a pulmonary inflammatory process, consisting of various cell types and mediators, resembling the typical inflammation found in transgenic mice infected with SARS-CoV-2. This inflammatory process was significantly decreased by the IN delivery of VitD, but not by its IP administration, suggesting that this hormone could have a therapeutic potential in COVID-19 if locally applied. To our knowledge, the local delivery of VitD to downmodulate lung inflammation in COVID-19 is an original proposition. Full article

The developmental origins of health and disease (DOHaD) indicate that fetal tissues and organs in critical and sensitive periods of development are susceptible to structural and functional changes due to the adverse environment in utero. Maternal immune activation (MIA) is one of the phenomena in DOHaD. Exposure to maternal immune activation is a risk factor for neurodevelopmental disorders, psychosis, cardiovascular diseases, metabolic diseases, and human immune disorders. It has been associated with increased levels of proinflammatory cytokines transferred from mother to fetus in the prenatal period. Abnormal immunity induced by MIA includes immune overreaction or immune response failure in offspring. Immune overreaction is a hypersensitivity response of the immune system to pathogens or allergic factor. Immune response failure could not properly fight off various pathogens. The clinical features in offspring depend on the gestation period, inflammatory magnitude, inflammatory type of MIA in the prenatal period, and exposure to prenatal inflammatory stimulation, which might induce epigenetic modifications in the immune system. An analysis of epigenetic modifications caused by adverse intrauterine environments might allow clinicians to predict the onset of diseases and disorders before or after birth. Full article

Cannabis use is continuously increasing in Canada, raising concerns about its potential impact on immunity. The current study assessed the impact of a cannabinoid mixture (CM) on B cells and the mechanisms by which the CM exerts its potential anti-inflammatory properties. Peripheral blood mononuclear cells (PBMCs) were treated with different concentrations of the CM to evaluate cytotoxicity. In addition, flow cytometry was used to evaluate oxidative stress, antioxidant levels, mitochondrial membrane potential, apoptosis, caspase activation, and the activation of key signaling pathways (ERK1/2, NF-κB, STAT5, and p38). The number of IgM- and IgG-expressing cells was assessed using FluoroSpot, and the cytokine production profile of the B cells was explored using a cytokine array. Our results reveal that the CM induced B-cell cytotoxicity in a dose-dependent manner, which was mediated by apoptosis. The levels of ROS and those of the activated caspases, mitochondrial membrane potential, and DNA damage increased following exposure to the CM (3 µg/mL). In addition, the activation of MAP Kinase, STATs, and the NF-κB pathway and the number of IgM- and IgG-expressing cells were reduced following exposure to the CM. Furthermore, the exposure to the CM significantly altered the cytokine profile of the B cells. Our results suggest that cannabinoids have a detrimental effect on B cells, inducing caspase-mediated apoptosis. Full article

Widespread vaccination using the oral live attenuated polio vaccine (OPV) and Sabin strain inactivated vaccine (sIPV) have greatly reduced the incidence of polio worldwide. In the period post-polio, the virulence of reversion of the Sabin strain makes the use of OPV gradually becoming one of the major safety hazards. The verification and release of OPV has become the top priority. The monkey neurovirulence test (MNVT) is the gold standard for detecting whether OPV meets the criteria, which are recommended by the WHO and Chinese Pharmacopoeia. Therefore, we statistically analyzed the MNVT results of type I and III OPV at different stages: 1996–2002 and 2016–2022. The results show that the upper and lower limits and C value of the qualification standard of type I reference products in 2016–2022 have decreased compared with the corresponding scores in the 1996–2002 period. The upper and lower limit and C value of the qualified standard of type III reference products were basically the same as the corresponding scores in the 1996–2002. We also found significant differences in the pathogenicity of the type I and III in the cervical spine and brain, with the decreasing trend in the diffusion index of the type I and type III in the cervical spine and brain. Finally, two evaluation criteria were used to judge the OPV test vaccines from 2016 to 2022. The vaccines all met the test requirements under the evaluation criteria of the above two stages. Based on the characteristics of OPV, data monitoring was one of the most intuitive methods to judge changes in virulence. Full article

Atherosclerosis is the formation of plaque within arteries due to overt assemblage of fats, cholesterol and fibrous material causing a blockage of the free flow of blood leading to ischemia. It is harshly impinging on health statistics worldwide because of being principal cause of high morbidity and mortality for several diseases including rheumatological, heart and brain disorders. Atherosclerosis is perpetuated by pro-inflammatory and exacerbated by pro-coagulatory mediators. Besides several other pathways, the formation of neutrophil extracellular traps (NETs) and the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contribute significantly to the initiation and propagation of atherosclerotic plaque for its worst outcomes. The present review highlights the contribution of these two disturbing processes in atherosclerosis, inflammation and atherothrombosis in their individual as well as collaborative manner. Full article

Several studies have reported on the negative implications of elevated neutrophil-to-lymphocyte ratio (NLR) and elevated platelet-to-lymphocyte ratio (PLR) levels associated with outcomes in many surgical and medical conditions, including cancer. In order to use the inflammatory markers NLR and PLR as prognostic factors in disease, a normal value in disease-free individuals must be identified first. This study aims (1) to establish mean values of various inflammatory markers using a healthy and nationally representative U.S. adult population and (2) to explore heterogeneity in the mean values by sociodemographic and behavioral risk factors to better specify cutoff points accordingly. The National Health and Nutrition Examination Survey (NHANES) of aggregated cross-sectional data collected from 2009 to 2016 was analyzed; data extracted included markers of systemic inflammation and demographic variables. We excluded participants who were under 20 years old or had a history of an inflammatory disease such as arthritis or gout. Adjusted linear regression models were used to examine the associations between demographic/behavioral characteristics and neutrophil counts, platelet counts, lymphocyte counts, as well as NLR and PLR values. The national weighted average NLR value is 2.16 and the national weighted average PLR value is 121.31. The national weighted average PLR value for non-Hispanic Whites is 123.12 (121.13–125.11), for non-Hispanic Blacks it is 119.77 (117.49–122.06), for Hispanic people it is 116.33 (114.69–117.97), and for participants of other races it is 119.84 (116.88–122.81). Non-Hispanic Blacks and Blacks have significantly lower mean NLR values (1.78, 95% CI 1.74–1.83 and 2.10, 95% CI 2.04–2.16, respectively) as compared with that of non-Hispanic Whites (2.27, 95% CI 2.22–2.30, p < 0.0001). Subjects who reported a non-smoking history had significantly lower NLR values than subjects who reported any smoking history and higher PLR values than current smokers. This study provides preliminary data for demographic and behavioral effects on markers of inflammation, i.e., NLR and PLR, that have been associated with several chronic disease outcomes, suggesting that different cutoff points should be set according to social factors. Full article

There is growing evidence of the association of Microscopic Colitis (MC) with the use of specific medications such as proton pump inhibitors (PPIs), Selective serotonin reuptake inhibitors (SSRIs), Non-Steroidal anti-inflammatory drugs (NSAIDs), Statins and H2-receptor antagonists (H2RA). In our study, we calculated the pooled odds of MC in patients using these drugs. We performed a detailed search of major databases, including PubMed/Medline, Scopus, web of science, and Embase, to include the studies in which odds of MC were reported after using above mentioned drugs. A random-effects model was used to pool the estimates. Thirteen studies were included in our analysis consisting of 304,482 patients (34,194 cases and 270,018 controls). In eight studies, the control group consisted of a random population selected based on age, gender and same birth year, whereas 3 studies recruited patients who presented with diarrhea and underwent colonoscopy and biopsy to rule out MC. Two studies reported odds of MC for both diarrhea and random control groups. Patients taking PPIs were more likely to develop MC, AOR 2.65 (95% CI 1.81–3.50, I² 98.13%). Similarly, higher odds of association were found in patients taking SSRIs (OR 2.12, 95% CI 1.27–2.96, I² 96.46%), NSAIDs (OR 2.02, 95% CI 1.33–2.70, I² 92.70%) and Statins (OR 1.74, 95% CI 1.19–2.30, I² 96.36%). No difference in odds of developing MC was seen in patients using H2RA compared to the control group (OR 2.70, 95% CI 0.32–5.08, I² 98.67%). We performed a subgroup analysis based on the control group and found higher odds of MC in patients on PPIs compared to the random control group (OR 4.55, 95% CI 2.90–6.19, I² 98.13%). Similarly, higher odds of MC were noted for SSRI (OR 3.23, 95% CI 1.54–4.92, I² 98.31%), NSAIDs (OR 3.27, 95% CI 2.06–4.48, I² 95.38%), and Statins (OR 2.23, 95% CI 1.41–3.06, I² 98.11%) compared to the random control group. Contrary lower odds of MC were seen in the PPI and H2RA group compared to the diarrhea control group (OR 0.68, 95% CI 0.48–0.88, I² 7.26%), (OR 0.46, 95% CI 0.14–0.78, I² 0%) respectively. We found no difference in odds of MC in patients on SSRIs (OR 0.96, 95% CI 0.49–1.42, I² 37.89%), NSAIDs (OR 1.13, 95% CI 0.49–1.76, I² 59.37%) Statins (OR 0.91, 95% 0.66–1.17, I² 0%) and H2RA (OR 3.48, 95% CI −0.41–7.36, I² 98.89%) compared to the diarrhea control group. We also analyzed the association use of PPIs and NSAIDs with the development of collagenous colitis (CC) and lymphocytic colitis. Only the use of NSAIDs was associated with increased odds of developing collagenous colitis (OR 1.61, 95% CI 1.50–1.72, I² 0%). No increased odds of CC and LC were seen in PPI users. PPIs, NSAIDs, SSRIs, and Statins are associated with an increased risk of MC compared to the random control group. On the contrary, the use of PPIs, NSAIDs, SSRIs, and Statins is not associated with an increased risk of MC when compared to the diarrhea control group. Full article

Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Mechanistic investigations into sepsis have mainly focused on targeting inflammatory pathways; however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulations that take place in sepsis might uncover novel therapeutic opportunities. The role of peroxisome proliferator-activated receptor alpha (PPARɑ) in liver dysfunction during sepsis has recently been described, and restoring PPARɑ signaling has proven to be successful in mouse polymicrobial sepsis. To confirm that such therapy might be translated to septic patients, we analyzed metabolic perturbations in the liver of a porcine fecal peritonitis model. Resuscitation with fluids, vasopressor, antimicrobial therapy and abdominal lavage were applied to the pigs in order to mimic human clinical care. By using RNA-seq, we detected downregulated PPARɑ signaling in the livers of septic pigs and that reduced PPARɑ levels correlated well with disease severity. As PPARɑ regulates the expression of many genes involved in fatty acid oxidation, the reduced expression of these target genes, concomitant with increased free fatty acids in plasma and ectopic lipid deposition in the liver, was observed. The results obtained with pigs are in agreement with earlier observations seen in mice and support the potential of targeting defective PPARɑ signaling in clinical research. Full article

Retinoid-related orphan receptor γt (RORγt), a vital transcription factor for the differentiation of the pro-inflammatory Th17 cells, is essential to the inflammatory response and pathological process mediated by Th17 cells. Pharmacological inhibition of the nuclear receptor RORγt provides novel immunomodulators for treating Th17-driven autoimmune diseases and organ transplant rejection. Here, we identified 2,2′,4′-trihydroxychalcone (TDC), a natural chalcone derivant, binds directly to the ligand binding domain (LBD) of RORγt and inhibited its transcriptional activation activity. Using three mice models of Th17-related diseases, it was found that the administration of TDC effectively alleviated the disease development of experimental autoimmune encephalomyelitis (EAE), experimental colitis, and skin allograft rejection. Collectively, these results demonstrated TDC targeting RORγt to suppress Th17 cell polarization, as well as its activity, thus, indicating the potential of this compound in treating of Th17-related autoimmune disorders and organ transplant rejection disorders. Full article

Mastitis is a common clinical disease which threatens the welfare and health of dairy cows and causes huge economic losses. Sanguinarine (SG) is a plant-derived alkaloid which has many biological functions, including antibacterial and antioxidant properties. The present study attempted to evaluate the effect of SG on lipopolysaccharide (LPS)-induced oxidative stress reactions and explore its potential mechanisms. The expression profile of SG was analyzed by network pharmacology, and it was found that differentially expressed genes were mainly involved in the Wnt signaling pathway and oxidative stress through GO and KEGG enrichment. In in vitro experiments, the dosage of SG was non-toxic to mouse mammary epithelial cells (mMECs) (p > 0.05). SG not only inhibited the increase in ROS induced by LPS, but also enhanced the activity of antioxidant enzymes (p < 0.05). Moreover, the results of the in vivo experiments showed that SG alleviated LPS-induced inflammatory damage of mouse mammary glands and enhanced the integrity of the blood–milk barrier (p < 0.05). Further studies suggested that SG promoted Nrf2 expression and suppressed the activation of the Wnt signaling pathway (p < 0.05). Conclusively, this study clarified the protective effect of SG on mastitis and provided evidence for new potential mechanisms. SG exerted its antioxidant function through activating Nrf2 and inhibiting the Wnt/β-catenin pathway, repairing the blood–milk barrier. Full article

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD. Full article

Zika virus (ZIKV) compromises placental integrity, infecting the fetus. However, the mechanisms associated with ZIKV penetration into the placenta leading to fetal infection are unknown. Cystatin B (CSTB), the receptor for advanced glycation end products (RAGE), and tyrosine-protein kinase receptor UFO (AXL) have been implicated in ZIKV infection and inflammation. This work investigates CSTB, RAGE, and AXL receptor expression and activation pathways in ZIKV-infected placental tissues at term. The hypothesis is that there is overexpression of CSTB and increased inflammation affecting RAGE and AXL receptor expression in ZIKV-infected placentas. Pathological analyses of 22 placentas were performed to determine changes caused by ZIKV infection. Quantitative proteomics, immunofluorescence, and western blot were performed to analyze proteins and pathways affected by ZIKV infection in frozen placentas. The pathological analysis confirmed decreased size of capillaries, hyperplasia of Hofbauer cells, disruption in the trophoblast layer, cell agglutination, and ZIKV localization to the trophoblast layer. In addition, there was a significant decrease in CSTB, RAGE, and AXL expression and upregulation of caspase 1, tubulin beta, and heat shock protein 27. Modulation of these proteins and activation of inflammasome and pyroptosis pathways suggest targets for modulation of ZIKV infection in the placenta. Full article

NLRP3 inflammasome-dependent pyroptosis has been implicated in liver fibrosis progression. However, the definite intrahepatic cell types that undergo pyroptosis and the underlying mechanism as well as the clinical importance remain unclear. Here, augmented levels of pyroptosis-related indicators GSDMD, IL-1β, and IL-18 were verified in both liver fibrosis patients and CCl4-induced fibrotic mouse model. Confocal imaging of NLRP3 with albumin, F4/80 or α-SMA revealed that enhanced NLRP3 was mainly localized to kupffer cells (KCs), indicating that KCs are major cell types that undergo pyroptosis. Targeting pyroptosis by inhibitor MCC950 attenuated the severity and ameliorated liver function in fibrosis models. In addition, elevated S100A8 in liver fibrosis patients was correlated with pyroptosis-related indicators. S100A8 stimulated pyroptotic death of macrophages, which resulted in activation of human hepatic stellate cell line LX-2 cells and increased collagen deposition. Mechanistically, S100A8 activated TLR4/NF-κB signaling and upregulated its target genes NLRP3, pro-IL-1β, and pro-IL-18 expression, and induced reactive oxygen (ROS) abundance to activate NLRP3 inflammasome, finally leading to pyroptotic cell death in macrophages. More importantly, circulating GSDMD had the optimal predicting value for liver fibrosis progression. In conclusion, S100A8-mediated NLRP3 inflammasome-dependent pyroptosis by TLR4/NF-κB activation and ROS production in macrophages facilitates liver fibrosis progression. The identified GSDMD has the potential to be a biomarker for liver fibrosis evaluation. Full article

Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host’s immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host–pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8⁺ and CD4⁺ T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of individuals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention. Full article

Tuberculosis is a stern, difficult to treat chronic infection caused by acid-fast bacilli that tend to take a long time to be eradicated from the host’s environment. It requires the action of both innate and adaptive immune systems by the host. There are various pattern recognition receptors present on immune cells, which recognize foreign pathogens or its product and trigger the immune response. The epigenetic modification plays a crucial role in triggering the susceptibility of the host towards the pathogen and activating the host’s immune system against the invading pathogen. It alters the gene expression modifying the genetic material of the host’s cell. Epigenetic modification such as histone acetylation, alteration in non-coding RNA, DNA methylation and alteration in miRNA has been studied for their influence on the pathophysiology of tuberculosis to control the spread of infection. Despite several studies being conducted, many gaps still exist. Herein, we discuss the immunopathophysiological mechanism of tuberculosis, the essentials of epigenetics and the recent encroachment of epigenetics in the field of tuberculosis and its influence on the outcome and pathophysiology of the infection. Full article

Small bowel and ileocecal diseases remain a diagnostic and therapeutic challenge, despite the introduction of various modalities for deep enteroscopy. Novel Motorized Spiral Enteroscopy is an innovative technology that uses an overtube with a raised spiral at the distal end to pleat the small intestine. It consumes less time and meets both the diagnostic and therapeutic needs of small bowel diseases. The objective of this article is to highlight the possibility of using NMSE as an alternative technique when a target lesion is inaccessible during conventional colonoscopy or cecal intubation cannot be achieved. We report the case of a 61-year-old man who presented with pain in the right lower abdominal segment, diarrhea, and rapid weight loss for more than 3 months. An initial ultrasound showed a suspicious liver metastasis. Computerized tomography scans showed an extensive ileocecal tumor mass with liver metastasis. The colonoscopy was unsuccessful and incomplete due to dolichocolon and intestinal tortuosity. Later, endoscopy was performed using a Novel Motorized Spiral Enteroscope in a retrograde approach, passing the scope through the anus and colon up to the ileocecal segment, where a tumor biopsy was performed and adenocarcinoma was pathohistologically confirmed. Full article

Here, we aim to describe COVID-19 pathology across different tissues to clarify the disease’s pathophysiology. Lungs, kidneys, hearts, and brains from nine COVID-19 autopsies were compared by using antibodies against SARS-CoV-2, macrophages-microglia, T-lymphocytes, B-lymphocytes, and activated platelets. Alzheimer’s Disease pathology was also assessed. PCR techniques were used to verify the presence of viral RNA. COVID-19 cases had a short clinical course (0–32 days) and their mean age was 77.4 y/o. Hypoxic changes and inflammatory infiltrates were present across all tissues. The lymphocytic component in the lungs and kidneys was predominant over that of other tissues (p < 0.001), with a significantly greater presence of T-lymphocytes in the lungs (p = 0.020), which showed the greatest presence of viral antigens. The heart showed scant SARS-CoV-2 traces in the endothelium–endocardium, foci of activated macrophages, and rare lymphocytes. The brain showed scarce SARS-CoV-2 traces, prominent microglial activation, and rare lymphocytes. The pons exhibited the highest microglial activation (p = 0.017). Microthrombosis was significantly higher in COVID-19 lungs (p = 0.023) compared with controls. The most characteristic pathological features of COVID-19 were an abundance of T-lymphocytes and microthrombosis in the lung and relevant microglial hyperactivation in the brainstem. This study suggests that the long-term sequelae of COVID-19 derive from persistent inflammation, rather than persistent viral replication. Full article

Inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the intestines. The underlying inflammation activates the coagulation cascade leading to an increased risk of developing arterial and venous thromboembolic events such as deep vein thrombosis and pulmonary embolism. Patients with IBD are at a 2–3-fold increased risk of developing thromboembolism. This risk increases in patients with active IBD disease, flare-ups, surgery, steroid treatment, and hospitalization. These complications are associated with significant morbidity and mortality making them important in clinical practice. Clinicians should consider the increased risk of thromboembolic events in patients with IBD and manage them with appropriate prophylaxis based on the risk. In this review, we discuss the literature associated with the pathophysiology of thromboembolism in patients with IBD, summarize the studies describing the various thromboembolic events, and the management of thromboembolism in patients with IBD. Full article

The prevalence of obesity has reached alarming levels, which is considered a major risk factor for several metabolic diseases, including type 2 diabetes (T2D), non-alcoholic fatty liver, atherosclerosis, and ischemic cardiovascular disease. Obesity-induced chronic, low-grade inflammation may lead to insulin resistance, and it is well-recognized that macrophages play a major role in such inflammation. In the current review, the molecular mechanisms underlying macrophages, low-grade tissue inflammation, insulin resistance, and T2D are described. Also, the role of macrophages in obesity-induced insulin resistance is presented, and therapeutic drugs and recent advances targeting macrophages for the treatment of T2D are introduced. Full article

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD. Full article

The plasma protein histidine-rich glycoprotein (HRG) is implicated in the polarization of macrophages to an M1 antitumoral phenotype. The broadly expressed secreted protein stanniocalcin 2 (STC2), also implicated in tumor inflammation, is an HRG interaction partner. With the aim to biochemically characterize the HRG and STC2 complex, binding of recombinant HRG and STC2 preparations to each other and to cells was explored using the quartz crystal microbalance (QCM) methodology. The functionality of recombinant proteins was tested in a phagocytosis assay, where HRG increased phagocytosis by monocytic U937 cells while STC2 suppressed HRG-induced phagocytosis. The binding of HRG to STC2, measured using QCM, showed an affinity between the proteins in the nanomolar range, and both HRG and STC2 bound individually and in combination to vitamin D3-treated, differentiated U937 monocytes. HRG, but not STC2, also bound to formaldehyde-fixed U937 cells irrespective of their differentiation stage in part through the interaction with heparan sulfate. These data show that HRG and STC2 bind to each other as well as to U937 monocytes with high affinity, supporting the relevance of these interactions in monocyte/macrophage polarity. Full article

Chronic infection by high-risk human papillomaviruses (HPV) and chronic inflammation are factors associated with the onset and progression of several neoplasias, including cervical cancer. Oncogenic proteins E5, E6, and E7 from HPV are the main drivers of cervical carcinogenesis. In the present article, we review the general mechanisms of HPV-driven cervical carcinogenesis, as well as the involvement of cyclooxygenase-2 (COX-2)/prostaglandin E₂ (PGE₂) and downstream effectors in this pathology. We also review the evidence on the crosstalk between chronic HPV infection and PGE₂ signaling, leading to immune response weakening and cervical cancer development. Finally, the last section updates the current therapeutic and preventive options targeting PGE₂-derived inflammation and HPV infection in cervical cancer. These treatments include nonsteroidal anti-inflammatory drugs, prophylactic and therapeutical vaccines, immunomodulators, antivirals, and nanotechnology. Inflammatory signaling pathways are closely related to the carcinogenic nature of the virus, highlighting inflammation as a co-factor for HPV-dependent carcinogenesis. Therefore, blocking inflammatory signaling pathways, modulating immune response against HPV, and targeting the virus represent excellent options for anti-tumoral therapies in cervical cancer. Full article