Extracellular matrix (ECM) is a complex network of macromolecules such as proteoglycans (PGs), glycosaminoglycans (GAGs) and fibrous proteins present within all tissues and organs. The main role of ...ECM is not only to provide an essential mechanical scaffold for the cells but also to mediate crucial biochemical cues that are required for tissue homeostasis. Dysregulations in ECM deposition alter cell microenvironment, triggering the onset or the rapid progression of several diseases, including cancer. Hyaluronan (HA) is a ubiquitous component of ECM considered as one of the main players of cancer initiation and progression. This review discusses how HA participate in and regulate several aspects of tumorigenesis, with particular attention to the hallmarks of cancer proposed by Hanahan and Weinberg such as sustaining of the proliferative signaling, evasion of apoptosis, angiogenesis, activation of invasion and metastases, reprogramming of energy metabolism and evasion of immune response.
Weinhofer et al. reveal impaired plasticity of macrophages, with intrinsic pro-inflammatory skewing and a decreased ability to establish proper anti-inflammatory responses, in X-linked ...adrenoleukodystrophy (ALD). This may contribute to the rapidly progressive demyelination seen in cerebral ALD.
Abstract
X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses, thus possibly contributing to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy that only in rare cases arrests spontaneously. These findings emphasize monocytes/macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy.
Since December 2019, SARS-CoV-2 infection has been still rapidly spreading, resulting in a pandemic, followed by an increasing number of cases in countries throughout the world. The severity of the ...disease depends on the patient's overall medical condition but no appropriate markers are available to establish the prognosis of the patients. We performed a 16S rRNA gene sequencing, revealing an altered composition of the nasal/oropharyngeal (NOP) microbiota in 21 patients affected by COVID-19, paucisymptomatic or in an Intensive Care Unit (ICU), as compared to 10 controls negative for COVID-19 or eight affected by a different Human Coronavirus (HKU, NL63 and OC43). A significant decrease in Chao1 index was observed when patients affected by COVID-19 (in ICU) were compared to paucisymptomatic. Furthermore, patients who were in ICU, paucisymptomatic or affected by other Coronaviruses all displayed a decrease in the Chao1 index when compared to controls, while Shannon index significantly decreased only in patients under ICU as compared to controls and paucisymptomatic patients. At the phylum level, Deinococcus-Thermus was present only in controls as compared to SARS-CoV-2 patients admitted to ICU, paucisymptomatic or affected by other coronaviruses. Candidatus Saccharibacteria (formerly known as TM7) was strongly increased in negative controls and SARS-CoV-2 paucisymptomatic patients as compared to SARS-CoV-2 ICU patients. Other modifications were observed at a lower taxonomy level. Complete depletion of Bifidobacterium and Clostridium was exclusively observed in ICU SARS-CoV-2 patients, which was the only group characterized by the presence of Salmonella, Scardovia, Serratia and Pectobacteriaceae. In conclusion, our preliminary results showed that nasal/oropharyngeal microbiota profiles of patients affected with SARS-CoV-2 may provide valuable information in order to facilitate the stratification of patients and may open the way to new interventional strategies in order to ameliorate the outcome of the patients.
Plasmodium ovale malaria is usually considered a tropical infectious disease associated with low morbidity and mortality. However, severe disease and death have previously been reported.
A case of ...severe P. ovale malaria in a healthy Caucasian man with a triangle splenic infarction and clinical progression towards Acute Respiratory Distress Syndrome was reported despite a rapid response to oral chloroquine treatment with 24-h parasitaemia clearance.
Plasmodium ovale malaria is generally considered as a benign disease, with low parasitaemia. However, severe disease and death have occasionally been reported. It is important to be aware that occasionally it can progress to serious illness and death even in immunocompetent individuals.
COronaVIrus Disease-2019 (COVID-19) is a pandemic respiratory infection caused by a new betacoronavirus, the Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2). Few data are reported on the ...gut microbiota in COVID-19 patients. 16S rRNA gene sequencing was performed to reveal an altered composition of the gut microbiota in patients with COVID-19 pneumonia admitted in intensive care unit (ICU) (i-COVID19), or in infectious disease wards (w-COVID19) as compared to controls (CTRL). i-COVID19 patients showed a decrease of Chao1 index as compared to CTRL and w-COVID19 patients indicating that patients in ICU displayed a lower microbial richness while no change was observed as for Shannon Index. At the phylum level, an increase of Proteobacteria was detected in w-COVID19 patients as compared to CTRL. A decrease of Fusobacteria and Spirochetes has been found, with the latter decreased in i-COVID19 patients as compared to CTRL. Significant changes in gut microbial communities in patients with COVID-19 pneumonia with different disease severity compared to CTRL have been identified. Our preliminary data may provide valuable information and promising biomarkers for the diagnosis of the disease and, when validated in larger cohort, it could facilitate the stratification of patients based on the microbial signature.
We report phylogenetic and mutational analysis of severe acute respiratory syndrome coronavirus 2 virus strains from the Lazio region of Italy and provide information about the dynamics of virus ...spread. Data suggest effective containment of clade V strains, but subsequently, multiple waves of clade G strains were circulating widely in Europe.
Heparan Sulfate in the Tumor Microenvironment Bartolini, Barbara; Caravà, Elena; Caon, Ilaria ...
Advances in experimental medicine and biology,
01/2020, Volume:
1245
Journal Article
Peer reviewed
The biology of tumor cells strictly depends on their microenvironment architecture and composition, which controls the availability of growth factors and signaling molecules. Thus, the network of ...glycosaminoglycans, proteoglycans, and proteins known as extracellular matrix (ECM) that surrounds the cells plays a central role in the regulation of tumor fate. Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPGs) are highly versatile ECM components that bind and regulate the activity of growth factors, cell membrane receptors, and other ECM molecules. These HS binding partners modulate cell adhesion, motility, and proliferation that are processes altered during tumor progression. Modification in the expression and activity of HS, HSPGs, and the respective metabolic enzymes results unavoidably in alteration of tumor cell microenvironment. In this light, the targeting of HS structure and metabolism is potentially a new tool in the treatment of different cancer types.
The presence of iduronic acid in chondroitin/dermatan sulfate changes the properties of the polysaccharides because it generates a more flexible chain with increased binding potentials. Iduronic acid ...in chondroitin/dermatan sulfate influences multiple cellular properties, such as migration, proliferation, differentiation, angiogenesis and the regulation of cytokine/growth factor activities. Under pathological conditions such as wound healing, inflammation and cancer, iduronic acid has diverse regulatory functions. Iduronic acid is formed by two epimerases (i.e. dermatan sulfate epimerase 1 and 2) that have different tissue distribution and properties. The role of iduronic acid in chondroitin/dermatan sulfate is highlighted by the vast changes in connective tissue features in patients with a new type of Ehler–Danlos syndrome: adducted thumb‐clubfoot syndrome. Future research aims to understand the roles of the two epimerases and their interplay with the sulfotransferases involved in chondroitin sulfate/dermatan sulfate biosynthesis. Furthermore, a better definition of chondroitin/dermatan sulfate functions using different knockout models is needed. In this review, we focus on the two enzymes responsible for iduronic acid formation, as well as the role of iduronic acid in health and disease.
The presence of iduronic acid in chondroitin/dermatan sulfate is important for multiple cellular properties such as migration, proliferation, differentiation, angiogenesis and regulation of cytokine/growth factor activities. Dermatan sulfate epimerase 1 and 2 and 4‐O‐sulfotransferase 1 are the dermatan biosynthetic enzymes whose roles in normal and pathophysiological situations are described in the review.
Hyaluronan (HA) is a glycosaminoglycan present in most tissue microenvironments that can modulate many cell behaviors, including proliferation, migration, and adhesive proprieties. In contrast with ...other glycosaminoglycans, which are synthesized in the Golgi, HA is synthesized at the plasma membrane by one or more of the three HA synthases (HAS1–3), which use cytoplasmic UDP-glucuronic acid and UDP-N-acetylglucosamine as substrates. Previous studies revealed the importance of UDP-sugars for regulating HA synthesis. Therefore, we analyzed the effect of UDP-GlcNAc availability and protein glycosylation with O-linked N-acetylglucosamine (O-GlcNAcylation) on HA and chondroitin sulfate synthesis in primary human aortic smooth muscle cells. Glucosamine treatment, which increases UDP-GlcNAc availability and protein O-GlcNAcylation, increased synthesis of both HA and chondroitin sulfate. However, increasing O-GlcNAcylation by stimulation with O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate without a concomitant increase of UDP-GlcNAc increased only HA synthesis. We found that HAS2, the main synthase in aortic smooth muscle cells, can be O-GlcNAcylated on serine 221, which strongly increased its activity and its stability (t½ >5 h versus ∼17 min without O-GlcNAcylation). S221A mutation prevented HAS2 O-GlcNAcylation, which maintained the rapid turnover rate even in the presence of GlcN and increased UDP-GlcNAc. These findings could explain the elevated matrix HA observed in diabetic vessels that, in turn, could mediate cell dedifferentiation processes critical in vascular pathologies.
Background: UDP-GlcNAc is a precursor of glycoconjugates, including hyaluronan, and induces protein glycosylation to form O-linked GlcNAc (O-GlcNAcylation).
Results: UDP-GlcNAc induces hyaluronan synthesis through O-GlcNAcylation of hyaluronan synthase 2, which stabilizes the enzyme and prevents its proteasomal degradation.
Conclusion:O-GlcNAcylation of hyaluronan synthase 2 can control synthesis of extracellular matrices with hyaluronan.
Significance: UDP-GlcNAc could control cell microenvironments that are altered in many pathologies, including vascular diseases and cancer.
The immune response to invading pathogens is characterized by the rapid establishment of a complex network of cellular interactions and soluble signals. The correct balancing of activating and ...regulating pathways and tissue-homing signals determines its effectiveness and persistence over time. Emerging viral pathogens have always represented a great challenge to the immune system and an often uncontrolled/imbalanced immune response has been described (e.g. cytokine storm, immune paralysis), contributing to the severity of the disease. Several immune biomarkers and cell subsets have been identified as major players in the cascade of events leading to severe diseases, highlighting the rationale for host-directed intervention strategy. There are millions of immunocompromised pediatric and adult patients worldwide (e.g. transplant recipients, hematologic patients, subjects with primary immune-deficiencies), experiencing an impaired immune reactivity, due to diseases and/or to the medical treatments. The reduced immune reactivity could have two paradoxical non-exclusive effects: a weak protective immunity on one hand, and a reduced contribution to immune-mediated pathogenetic processes on the other hand. In these sensitive contexts, the impact of emerging infections represents a still open issue to be explored with several challenges for immunologists, virologists, physicians and epidemiologists. In this review, we will address emerging infections in immunocompromised hosts, to summarize the available data concerning the immune response profile, its influence on the clinical presentation, the possible contribution of persistent viral shedding in generating new viral variants with improved immune escape features, and the key role of vaccination.
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