Medical Sciences — Open Access Journal

Macrophages are key players in various inflammatory disorders and pathological conditions via phagocytosis and orchestrating immune responses. They are highly heterogeneous in terms of their phenotypes and functions by adaptation to different organs and tissue environments. Upon damage or infection, monocytes are rapidly recruited to tissues and differentiate into macrophages. Transglutaminases (TGs) are a family of structurally and functionally related enzymes with Ca²⁺-dependent transamidation and deamidation activity. Numerous studies have shown that TGs, particularly TG2 and Factor XIII-A, are extensively involved in monocyte- and macrophage-mediated physiological and pathological processes. In the present review, we outline the current knowledge of the role of TGs in the adhesion and extravasation of monocytes, the expression of TGs during macrophage differentiation, and the regulation of TG2 expression by various pro- and anti-inflammatory mediators in macrophages. Furthermore, we summarize the role of TGs in macrophage phagocytosis and the understanding of the mechanisms involved. Finally, we review the roles of TGs in tissue-specific macrophages, including monocytes/macrophages in vasculature, alveolar and interstitial macrophages in lung, microglia and infiltrated monocytes/macrophages in central nervous system, and osteoclasts in bone. Based on the studies in this review, we conclude that monocyte- and macrophage-derived TGs are involved in inflammatory processes in these organs. However, more in vivo studies and clinical studies during different stages of these processes are required to determine the accurate roles of TGs, their substrates, and the mechanisms-of-action. Full article

We review current management for allergic rhinitis and possible new treatments for this condition. Management of allergic rhinitis includes promotion of protective factors, avoidance of allergens, and possibly immunotherapy. In recent years, the incidence of allergic rhinitis has increased in many countries. Early intervention at different stages is an important part of management. Allergic disease in infants has been described as the allergic march, commencing with atopic dermatitis accompanied by infantile asthma and progressing to perennial allergic rhinitis induced by house dust mite allergy. In order to prevent polysensitization, allergen-specific immunotherapy should probably be initiated at an earlier age, especially in children with rhinitis who show monosensitization to house dust mite antigens. Full article

Bladder cancer is the 10th-most common cancer worldwide. The diagnosis and follow-up of patients require costly invasive methods and due to these expenses, bladder cancer continues to be one of the expensive malignancies. Early diagnosis is crucial in bladder cancer as it is in other cancers; therefore, non-invasive biomarkers for early diagnosis are very important. In this review, we aimed to focus on the most recent investigations on potential urinary micro RNA (miRNA) and protein biomarkers for bladder cancer diagnosis and their associated pathways. Studies performed by different groups were compiled and the biomarker properties of various proteins and miRNAs in the urine of bladder cancer patients were evaluated. Key studies were obtained by searching keywords “bladder cancer, urinary miRNA, urinary protein, urinary biomarker”. Targets and the pathways of the miRNAs and proteins were analyzed according to mirBase Catalogue and Panther Database. The major pathways that are targeted by aberrantly expressed miRNAs are Cholecystokinin receptor (CCKR), p53, Wnt signaling pathway, and feedback loops. We hereby conclude that urinary micro RNAs and proteins are promising candidates for bladder cancer diagnosis. It should be noted that urine collection, storage conditions, choice of fraction, and normalization strategies should be standardized. Full article

Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, SMS deficiency causes a lack of spermine with an accumulation of spermidine. As polyamines, spermine, and spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on polyamine homeostatic mechanisms including polyamine biosynthetic and catabolic enzymes, derivatives of the natural polyamines, and polyamine transport activity. In addition to decreased spermine and increased spermidine in SRS cells, ornithine decarboxylase activity and its product putrescine were significantly decreased. Treatment of SRS cells with exogenous spermine revealed that polyamine transport was active, as the cells accumulated spermine, decreased their spermidine level, and established a spermidine-to-spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of tissue transglutaminase, a change associated with certain neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of Snyder-Robinson Syndrome. Full article

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It is characterized by a chronic, progressive, fibrotic interstitial lung disease of unknown cause that occurs primarily in older adults. Its prevalence and incidence have appeared to be increasing over the last decades. Despite its unknown nature, several genetic and environmental factors have been associated with IPF. Moreover, its natural history is variable, but could change depending on the currently suggested phenotypes: rapidly progressive IPF, familial, combined pulmonary fibrosis and emphysema, pulmonary hypertension, and that associated with connective tissue diseases. Early recognition and accurate staging are likely to improve outcomes and induce a prompt initiation of antifibrotics therapy. Treatment is expected to be more effective in the early stages of the disease, while developments in treatment aim to improve the current median survival of 3–4 years after diagnosis. Full article

The launch of ‘Rapid Recommendations’ by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) group, in collaboration with Making GRADE the Irresistible Choice (MAGIC) and the British Medical Journal (BMJ), is a very interesting recent development in e-healthcare. Designed to respond quickly to developments that have created new decision situations, their first project resulted from the arrival of minimally invasive Transcatheter Aortic Valve Implantation (TAVI) as an alternative to Surgical Aortic Valve Replacement (SAVR), for patients with symptomatic severe aortic stenosis. The interactive MAGIC decision aid that accompanies a Rapid Recommendation and is the main route to its clinical implementation, represents a major advance in e-health, for a cardiovascular decision in this case. However, it needs to go further in order to facilitate fully person-centred care, where the weighted preferences of the individual person are elicited at the point of decision, and transparently integrated with the best (most personalised) estimates of option performances, to produce personalised, preference-sensitive option evaluations. This can be achieved by inputting the collated GRADE evidence on the criteria relevant in the TAVI/SAVR choice into a Multi-Criteria Decision Analysis-based decision support tool, generating a personalised, preference-sensitive opinion. A demonstration version of this add-on to the MAGIC aid, divested of recommendations, is available online as proof of method. Full article

Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system (CNS) characterized by inflammation and immune cell infiltration in the brain parenchyma. Tissue transglutaminase (TG2), a calcium-dependent cross-linking enzyme, has been shown to be present in infiltrating MHC-II positive cells in lesions of patients suffering from MS. Moreover, TG2 mRNA levels in peripheral blood mononuclear cells (PBMC)-derived from primary progressive (PP)-MS patients correlated with clinical parameters, thus highlighting the importance of TG2 in MS pathology. In the present study, we further characterized TG2 expression by measuring the mRNA levels of full-length TG2 and four TG2 alternative splice variants in PBMCs derived from PP-MS patients and healthy control (HC) subjects. In PP-MS-derived PBMCs, TG2 variant V4b was significantly higher expressed, and both V4a and V4b variants were relatively more expressed in relation to full-length TG2. These observations open new avenues to unravel the importance of TG2 alternative splicing in the pathophysiology of PP-MS. Full article

OK-432, a preparation of a low-virulence strain (Su) of Streptococcus pyogenes (Group A) killed by a penicillin and lyophilized, is a stiff inducer of Th1 cytokines, and exerts anti-cancer effects in tumor-bearing mice. OK-432 has been reported to consist of many bacterial components, such as peptidoglycan, M-protein, etc. However, it is yet to be ascertained which bacterial component induces T helper 1 (Th1) responses. For the last decade, Toll-like receptor (TLR) family proteins are well elucidated to play a role in recognizing bacterial components and inducing interleukin (IL)-12 from macrophages. Above all, peptidoglycan seems to be the agonist of TLR2 rather than the obverse. In our present study, the role of TLR2 for the recognition of OK-432 by macrophages and the effects of OK-432 are examined on murine allergic rhinitis model. Interestingly, results show IL-12 production by macrophages derived from TLR2 knock-out (ko) mice was significantly decreased, in comparison with that of macrophages derived from wild-type mice. Moreover, in TLR2 ko mice, no regulatory effect of OK-432 was observed on an allergic rhinitis model. These data indicate that TLR2 signaling is involved in regulating OK-432-induced anti-T helper 2 (Th2) immunity, and may offer a new prophylactic and therapeutic approach using OK-432 to downregulate allergic disorders, such as allergic rhinitis. Full article

Peru is a country with wide regional disparities in health. Remote Amazonian communities have high rates of poverty and poor access to health services. There is a lack of data on morbidity and use of health services in the region. We describe a descriptive, cross-sectional study of the demographic characteristics and presenting complaints of attendees to a newly-opened primary care facility in a remote community. This was supplemented by structured interviews of adult attendees to build a picture of sociocultural determinants of health locally, including engagement with traditional forms of medicine. Our study provides novel insights into an under-studied and under-resourced area. We found a young population with a high prevalence of infectious illnesses, particularly dermatological infections - a previously under-recognised source of morbidity in these communities. Poor literacy rates and widespread use of traditional forms of medicine have important implications for the provision of healthcare in this region. Full article

Phospholipids (PLs), key elements of cellular membranes, are regulated reciprocally with membrane proteins and can act as sensors for alterations in physiological or pathological states of cells including initiation and development of cancer. On the other hand, peripheral blood mononuclear cells (MNCs) play an important role in antitumor immune response by reacting to cancerous modifications in distant organs. In the current study, we tested the hypothesis that tumor initiation and development are reflected in the alteration pattern of the MNC PL component. We analyzed MNC membrane PL fractions in samples from healthy individuals and from patients with diverse types of cancers to reveal possible alterations induced by malignancy. Compared to healthy controls, the cancer samples demonstrated shifts in several membrane PL profiles. In particular, when analyzing cancer data pooled together, there were significantly higher levels in lysophosphatidylcholine, phosphatidylcholine, and phosphatidylethanolamine fractions, and significantly lower quantities in phosphatidylinositol, phosphatidylserine, and phosphatidic acid fractions in cancer samples compared to controls. The levels of sphingomyelins and diphosphatidylglycerols were relatively unaffected. Most of the differences in PLs were sustained during the analysis of individual cancers such as breast cancer and chronic lymphocytic leukemia. Our findings suggest the presence of a common pattern of changes in MNC PLs during malignancy. Full article

Periodontal disease (PD), a chronic inflammatory condition characterized by destruction of the supporting tissues of the teeth, increases the risk of complications in diabetics. Diabetic retinopathy (DR) is a microvascular complication of prolonged hyperglycaemia. There appears to be a similarity in the pathogenesis of DR and PD. Hence, this study aimed to investigate the association, if any, between DR and PD, correlate the severity of DR with the severity of PD, and investigate the association between glycated haemoglobin (HbA1c), serum creatinine and periodontal variables. The periodontal status of 200 adult diabetic patients in the age group of 30–65 years with varying severity of DR was assessed. Evaluation of the severity of PD was assessed by recording clinical parameters. Haematological investigations including glycated haemoglobin (HbA1c) and serum creatinine were estimated before the initiation of treatment for DR. A statistically significant association between the mean duration of diabetes mellitus (DM) and the severity of DR and PD was found. The severity of PD was directly correlated with the severity of DR. There was a significant association between the levels of HbA1c and serum creatinine and severity of DR and PD. There could be a plausible relationship between DR and PD. Further prospective studies on a larger population with longer follow-ups are required to ascertain whether PD and its severity directly affect the progression and severity of DR. Full article

Recent evidence indicated that transglutaminase 2 (TG2) is involved in the adaptive immune response. Peripheral blood mononuclear cells (PBMC) have largely been used to characterize molecular mechanisms occurring in the activation of immune response. Given that the maintenance of immune system functions requires an optimal vitamin D status, we aimed to assess the involvement of TG2/NF-κB signaling in cytokine production in PBMC isolated from adult subjects with different vitamin D status. We observed TG2 up-regulation and a significant positive correlation between TG2 expression and tumor necrosis factor (TNF)-α mRNA levels in PBMC of recruited patients. The mRNA levels of TG2 and TNF-α were higher in PBMC of subjects having hypovitaminosis D, namely plasma 25(OH)vitamin D3 levels lower than 50 nmol/L, than in those with normal vitamin D levels. Moreover, NF-κB up-regulation and nuclear translocation were detected, concomitantly with TG2 as well as TNF-α increased expression, in PBMC of vitamin D-deficient subjects. The present findings confirm that an increase in TG2 expression exacerbates the activation of NF-κB and the production of pro-inflammatory cytokines, and suggest a link between vitamin D deficiency, TG2 up-regulation, and inflammation. Full article

Antiphospholipid syndrome (APS) is a multifactorial, autoantibody-mediated disease. Antiphospholipid antibodies (aPL) directed against negatively charged phospholipids or various combinations of phospholipid-binding proteins seem to be an independent pathogenic factor that plays a critical role in APS. Unfortunately, their role in hypertension is not fully elucidated. The aim of our study was to determine aPL titers in hypertension patients and investigate the association of aPL with renal impairment parameters. Forty-seven patients with arterial hypertension (22 males, 46.8% and 25 females, 53.2%), aged 41–85 years old (mean 65.9 ± 10.1 years), and 21 age-sex-matched subjects without severe hypertension as control group (8 males, 13 females, 38.1% vs. 61.9%), mean age 61 ± 11.3 years, were enrolled in this study. Patients with other risk factors like Rheumatoid Arthritis and Systematic Lupus Erythematosus (SLE), both viral and bacterial acute infections, and cancer were excluded from the study. The aPL (anticardiolipin (ACA) and anti-b2GPI antibodies, IgG and IgM) were measured by ELISA (Aesculisa, Aesku Diagnostics, Wendelsheim, Germany) with a cutoff of 15 GPL/MPL for ACA and 15 U/mL for b2GPI. Serum Neutrophil gelatinase-associated lipocalin (sNGAL) was measured by ELISA kits (BioVendor, Brno, Czech Republic). Biochemical analysis such as serum creatinine (Cr), were measured by automated analyzer and finally estimated glomerular filtration rate (e-GFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Fifteen patients were positive for ACA IgG (31.9%), two for anti-b2GPI IgM (4.2%), and three for anti-b2GPI IgG (6.3%). Furthermore, three persons from control group were positive in anti-b2GPI IgG (14.27%). The serum level of anti-b2GPI IgG was significantly higher in patients compared to healthy controls (p = 0.013). The level of sNGAL (59.63 ± 41.5 ng/mL vs. 45.5 ± 21.5 ng/mL, p = 0.14) was not higher in hypertensive patients than in the age-sex-matched control group. Additionally, the sNGAL level was found to be directly and positively correlated in patients with positive ACA IgG (r² = 0,945, p < 0.0001). These results demonstrate that autoimmunity may be one of the pathogenetic factors of hypertension and aPL antibodies might be a potential marker of renal involvement. Full article

The utility of the adenosine deaminase (ADA) assay in the diagnosis of patients with pleural tuberculosis (TB) and human immunodeficiency virus (HIV) infection is controversial. Forty-eight HIV positive patients with pleural effusion were evaluated; ADA assay was obtained in forty-three of them. Twenty-five patients presented diagnosis of TB. Patients with diagnosis of TB showed a median value of ADA of 70 IU/L (interquartile range (IQR) 41–89) and the non-TB group a median of 27.5 IU/L (IQR 13.5–52). Patients with diagnosis of TB had a median cluster of differentiation 4 (CD4) count of 174 (IQR 86–274) and the non-TB group had a median of 134 (IQR 71–371). Receiver operating characteristic curve was performed with an area under the curve of 0.79. The best cut-off obtained was 35 IU/L with a sensibility of 80% and a specificity of 66%. There was no correlation between CD4 lymphocytes count and the value of ADA in the TB patient group. Full article

With the advancement in the mechanism of immune surveillance and immune evasion in cancer cells, cancer immunotherapy shows promising results for treating cancer with established efficacy and less toxicity. As a result of the off-target effect, the approach for delivering vaccines, adjuvants, or antibodies directly to tumor sites is gaining widespread attention. An effective alternative is to utilize nanoengineered particles, functioning as drug-delivery systems or as antigens themselves. This article reviews the practical implementation of nanotechnology in cancer immunotherapy. Full article

Diabetic foot ulcers (DFU) are a major health problem associated with diabetes mellitus. Impaired nitric oxide (NO) production has been shown to be a major contributor to the dysregulation of healing in DFU. The level of impairment is not known primarily due to challenges with measuring NO. Herein, we report the actual level of NO produced by human dermal fibroblasts cultured under normal and high glucose conditions. Fibroblasts produce the extracellular matrix, which facilitate the migration of keratinocytes to close wounds. The results show that NO production was significantly higher in normal glucose compared to high glucose conditions. The real-time NO detected was compared to the nitrite present in the culture media and there was a direct correlation between real-time NO and nitrite in normal glucose conditions. However, real-time NO detection and nitrite measurement did not correlate under high glucose conditions. The inducible nitric oxide synthase (iNOS) enzyme responsible for NO production was upregulated in normal and high glucose conditions and the proliferation rate of fibroblasts was not statistically different in all the treatment groups. Relying only on nitrite to assess NO production is not an accurate determinant of the NO present in the wound bed in pathological states such as diabetes mellitus. Full article

Thrombophilia gene variants have been shown to be associated with higher risk of recurrent pregnancy loss (RPL). Due to the role of human platelets antigen 1 (HPA-1) and fibrinogen β chain (FGB) as critical players in the coagulation process, their most important variants including rs5918 T > C and rs1800790 G > A were selected to be studied in women affected by RPL. Three milliliters of peripheral blood were drawn from 110 women with history of at least two consecutive spontaneous abortion and 110 healthy women controls. rs5918 T > C and rs1800790 G > A of HPA-1 and FGB genes, respectively, were selected to be analyzed through polymerase chain reaction-restriction fragment length polymorphism (PCR_RFLP) following DNA isolation using QIAamp DNA Blood Mini Kit. Heterozygote genotype (TC) of HPA-1 gene rs5918 polymorphism was significantly associated with risk of RPL (p-value = 0.02). Although, rs1800790 G > A of FGB gene was not associated with RPL, its combination with rs5918 polymorphism was associated with increased risk of RPL. Owing to the critical roles of FGB and HPA-1 genes in coagulation, and thrombosis and several confinements on the meaningful association between the combination of those polymorphism with risk of RPL, including them in the thrombophilia panel may increase detection rate of hereditary thrombophilia patients. However, further studies with larger sample sizes are required to shed light on the exact role of the studied gene polymorphism, especially rs1800790 G > A of FGB gene variant in pathogenesis of RPL. Full article

It is speculated that lifestyle interventions known to improve diabetic metabolic state may exert their effects via adipokines. The aim of this systematic review and meta-analysis was to evaluate the chronic effects of physical exercise on adiponectin and leptin levels in adult prediabetic and diabetic individuals. PubMed, Embase, Scopus, The Cochrane Library, clinicaltrials.gov, and WHO Clinical Trials Registry were searched for randomized controlled trials. Pooled effects of interventions were assessed as mean difference (MD) with random effects model. Sensitivity analysis was conducted to test data robustness and subgroup analysis for study heterogeneity. Twenty-two trials with 2996 individuals were included in the meta-analysis. Physical exercise increased levels of adiponectin (MD: 0.42 µg/mL; 95% confidence interval (CI), 0.23, 0.60, p < 0.00001, n = 19 trials) and reduced leptin levels (MD: −1.89 ng/mL; 95% CI, −2.64, −1.14, p < 0.00001, n = 14 trials). These results were robust and remained significant after sensitivity analysis. Study heterogeneity was generally high. As for physical exercise modalities, aerobic exercise, but not other modalities, increased adiponectin and reduced leptin levels. In conclusion, physical exercise and, specifically, aerobic exercise, leads to higher adiponectin and lower leptin levels in prediabetic and diabetic adults. However, cautious interpretation of current findings is warranted. Full article