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HIV-1, like the other lentiviruses, has evolved the ability to infect nondividing cells including macrophages. HIV-1 replication in monocytes/macrophages entails peculiar features and differs in many respects from that in CD4 T lymphocytes. HIV-1 exhibits different tropism for CD4 T cells and macrophages. The virus can enter macrophages via several routes. Mitosis is not required for nuclear import of viral DNA or for its integration into the host cell genome. Specific cellular factors are required for HIV-1 transcription in macrophages. The assembly and budding of viral particles in macrophages take place in late endosomal compartments. Viral particles can use the exosome pathway to exit cells. Given their functions in host defence against pathogens and the regulation of the immune response plus their permissivity to HIV-1 infection, monocytes/macrophages exert a dual role in HIV infection. They contribute to the establishment and persistence of HIV-1 infection, and may activate surrounding T cells favouring their infection. Furthermore, monocytes/macrophages act as a Trojan horse to transmit HIV-1 to the central nervous system. They also exhibit antiviral activity and express many molecules that inhibit HIV-1 replication. Activated microglia and macrophages may also exert a neurotrophic and neuroprotective effect on infected brain regulating glutamate metabolism or by secretion of neurotrophins. This review will discuss specific aspects of viral replication in monocytes/macrophages and the role of their interactions with the cellular environment in HIV-1 infection swinging between protection and pathogenesis. [Copyright &y& Elsevier]

Abstract: The cancer risk assessment of peroxisome proliferators (PPs) has been a matter of debate for decades. PPs are non-genotoxic carcinogens that cause liver tumours in rodents. There is considerable evidence that humans are refractory to the carcinogenic effect of PPs. Still, some toxicologists argue that these chemicals should be considered carcinogenic until the opposite has been proven. To solve this matter, much work has been dedicated to uncovering the mode of action of PPs. The proceedings are reviewed and it is discussed whether these provide an explanation for the observed interspecies differences and shed a new light on human health risk assessment. The efforts in the past years have significantly increased our understanding of the pathways involved, but have also raised new questions. The question why humans seem to be refractory is yet to be answered. From this point of view, the safety assessment of PPs to humans therefore remains an issue of discussion. [Copyright &y& Elsevier]

Progress in defining protein and gene signatures that characterize autoimmune-mediated inflammatory diseases has uncovered a large number of potential therapeutic targets. Preclinical data from rodent models can be generated rapidly, as can data from the genetic crosses of gene-deficient mice on autoimmune-susceptible backgrounds. But humans are not the same as mice, and however robust preclinical data might appear, therapeutic intervention in patients with autoimmune disease remains the definitive experiment. Several studies published in the past year have tested paradigms of autoimmune disease in clinical trials. Recent therapeutic approaches for targeting B-cell subsets and co-stimulatory pathways are described here in detail. It is our belief that the future of immunotherapy in the clinic will depend to some extent upon the availability of biomarkers for defining biological signatures of immune function in vivo. [Copyright &y& Elsevier]

The expression of inflammatory genes in the heart plays an important role in organ dysfunction. However, the contribution of cardiomyocytes to this process, and in particular to the synthesis of high concentrations of nitric oxide and prostaglandins, has not been analyzed in detail. For this reason, cultured isolated cardiomyocytes were used to evaluate the response to pro-inflammatory stimuli.Isolated cultured foetal, neonatal, and adult rat cardiomyocytes were stimulated with lipopolysaccharide and cytokines, and the expression of nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) in these cells was investigated. Only cultured foetal cardiomyocytes expressed NOS-2 and COX-2 under these conditions, whereas the neonatal counterparts required various days in culture to gain this response. Analysis of the NF-κB signalling pathway showed an impaired activation of IκB kinase in response to lipopolysaccharide and cytokines in cells maintained in culture for 1 day. These data were confirmed by DNA microarray analysis. However, other early signalling pathways, such as the p38 and Erk MAPKs, were not affected by the time in culture.Neonatal and adult cardiomyocytes are resistant to the expression of pro-inflammatory genes due to impairment in the activation of IκB kinase, a process that might contribute to preventing rapid organ dysfunction in the course of various inflammatory pathologies, such as septic shock and myocarditis. [Copyright &y& Elsevier]

: Background/AimsStudies in acute liver failure show correlation between evidence of a systemic inflammatory response syndrome (SIRS) and progression of hepatic encephalopathy (HE). We tested the hypothesis that SIRS mediators, such as nitric oxide and proinflammatory cytokines, may exacerbate the neuropsychological effects of hyperammonemia in cirrhosis.: MethodsTen patients with cirrhosis were studied, 24–36 h after admission with clinical evidence of infection, and following its resolution. Hyperammonemia was induced by oral administration of an amino-acid (aa) solution mimicking hemoglobin composition. Inflammatory mediators, nitrate/nitrite, ammonia, aa profiles and a battery of neuropsychological tests were measured.: ResultsThe hyperammonemia generated in response to the aa solution was similar prior to, and after resolution, of the inflammation (P=0.77). With treatment of the infection there were significant reductions in white blood cell count (WBC), C-reactive protein (CRP), nitrate/nitrite, interleukin-6, interleukin-1β and tumour necrosis factor α. Induced hyperammonemia resulted in significant worsening of the neuropsychological scores when patients showed evidence of SIRS but not after its resolution.: ConclusionsThe significant deterioration of neuropsychological test scores following induced hyperammonemia during the inflammatory state, but not after its resolution, suggests that the inflammation and its mediators may be important in modulating the cerebral effect of ammonia in liver disease. [Copyright &y& Elsevier]

Background: Noninvasive diagnostics of nonalcoholic fatty liver disease (NAFLD), the most common cause of liver dysfunction in children, are based on imaging, biochemical tests and their compilation. The study aimed to evaluate the serological biomarkers of steatosis, inflammation and liver fibrosis to assess the risk of NAFLD in children., Methods: A total of 73 children were included in the prospective study; 50 of them were diagnosed with NAFLD based on ultrasound, and 23 formed a control group. Basic anthropometric parameters were measured, blood samples were taken for laboratory tests and evaluated proteins were assessed by enzyme-linked immunosorbent assay-adiponectin, tumour necrosis factor alpha, fibroblast growth factor 21, liver fatty acid-binding protein (L-FABP) and interleukin 6., Results: Statistically significant differences between the levels of two proteins were found: the adiponectin level was lower in the NAFLD group (12.24 ± 7.01 vs 16.88 ± 9.21 μg/mL, P  = 0.024), and L-FABP levels were higher (21.48 ± 20.61 vs 11.74 ± 8.39 ng/mL, P  = 0.031). In the group of children with body mass index (BMI)-for-age >1 standard deviation (SD), adiponectin concentration was also significantly lower (12.18 ± 6.43 μg/mL) than in the group with BMI ≤1 SD (17.29 ± 9.42 μg/mL, P  = 0.015). The odds ratios and 95% confidence interval for the relation between adiponectin and NAFLD and obesity were 0.868 (0.767-0.982) and 0.838 (0.719-0.977), respectively., Conclusion: Adiponectin may be useful in evaluating the risk of NAFLD and obesity in children., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Notch signaling is activated in the intestinal epithelial cells (IECs) of patients with inflammatory bowel disease (IBD), and contributes to mucosal regeneration. Our previous study indicated that TNF-α and Notch signaling may synergistically promote the expression of the intestinal stem cell (ISC) marker OLFM4 in human IECs. In the present study, we investigated the gene regulation and function of OLFM4 in human IEC lines. We confirmed that TNF-α and Notch synergistically upregulate the mRNA expression of OLFM4. Luciferase reporter assay showed that OLFM4 transcription is regulated by the synergy of TNF-α and Notch. At the protein level, synergy between TNF-α and Notch promoted cytoplasmic accumulation of OLFM4, which has potential anti-apoptotic properties in human IECs. Analysis of patient-derived tissues and organoids consistently showed cytoplasmic accumulation of OLFM4 in response to NF-κB and Notch activation. Cytoplasmic accumulation of OLFM4 in human IECs is tightly regulated by Notch and TNF-α in synergy. Such cytoplasmic accumulation of OLFM4 may have a cell-protective role in the inflamed mucosa of patients with IBD., Competing Interests: Authors have no conflict of interest to declare., (© 2021 The Authors. Published by Elsevier B.V.)

Tumor-promoting inflammation is one of the hallmarks of cancer. It has been shown that cancer development is strongly influenced by both chronic and acute inflammation process. Progress in research on inflammation revealed a connection between inflammatory processes and neoplastic transformation, the progression of tumour, and the development of metastases and recurrences. Moreover, the tumour invasive procedures (both surgery and biopsy) affect the remaining tumour cells by increasing their survival, proliferation and migration. One of the concepts explaining this phenomena is an induction of a wound healing response. While in normal tissue it is necessary for tissue repair, in tumour tissue, induction of adaptive and innate immune response related to wound healing, stimulates tumour cell survival, angiogenesis and extravasation of circulating tumour cells. It has become evident that certain types of immune response and immune cells can promote tumour progression more than others. In this review, we focus on current knowledge on carcinogenesis and promotion of cancer growth induced by inflammatory processes., (© 2020 The Author(s).)

Background/objectives: Soluble CD163 (sCD163), a macrophage activation marker, is upregulated in conditions of macrophage proliferation and activation. Elevated sCD163 levels have been associated with liver disease severity and progression. During liver transplantation, the implanted liver is exposed to ischaemia and reperfusion injury, resulting in an acute inflammatory response and macrophage activation. The relationship between sCD163 levels during liver transplantation and the development of early allograft dysfunction (EAD) has not been investigated., Methods: We included 27 cirrhosis patients (age 55 [range 32-72] years, 23 men) on the waiting list for liver transplantation. Alcohol consumption and viral hepatitis were the most frequent causes for cirrhosis. Patients were characterised by standard biochemical analysis and based on clinical disease severity scores. Information about donor, graft and course of the liver transplantation was recorded. sCD163 levels were measured at the time of liver transplantation before surgery, 2 h after reperfusion, and then at 24 h after transplantation., Results: We observed above-normal sCD163 levels at baseline (5.9 mg/L [4.7-8.8]). Two hours after reperfusion, sCD163 levels increased significantly from baseline (8.4 mg/L [7.4-10.9]; P  < 0.01). Twenty-four hours after transplantation, sCD163 levels were significantly reduced compared with baseline (3.7 mg/L [2.9-5.5]; P  < 0.01). However, in patients with EAD (n = 16), sCD163 levels were increased compared with patients without EAD (4.1 [3.2-7.4] vs. 3.1 [2.8-3.8] mg/L; P  = 0.03)., Conclusions: We observed elevated sCD163 levels in patients with EAD after liver transplantation, confirming macrophage activation to play a role in EAD. Thus, sCD163 may be used as an early marker for EAD after liver transplantation, but larger studies are warranted to validate these findings.