Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in amyotrophic lateral sclerosis (ALS)

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, responsible for the integrity of the basement membrane (BM) via degradation of extracellular matrix and BM components. These enzymes are presented in central and peripheral nervous system. They are considered to be involved in the pathogenesis of several neurological diseases, including amyotrophic lateral sclerosis (ALS). ALS is a motor neuron disease, leading to muscle atrophy, paralysis and death within 3–5 years from diagnosis. Currently, there is no treatment that can substantially prolong life of ALS patients. Despite the fact that MMPs are not specific for ALS, there is also strong evidence that these enzymes are involved in the pathology of ALS. MMPs are able to exert direct neurotoxic effects, or may cause cell death by degrading matrix proteins. The objective of this paper is to provide an updated and comprehensive review concerning the role of MMPs and their tissue inhibitors (TIMPs) in the pathology of ALS with an emphasis on the significance of MMP-2 and MMP-9 as well as their tissue inhibitors as potential biomarkers of ALS. Numerous hypotheses have been proposed regarding the role of selected MMPs and TIMPs in ALS pathogenesis. Moreover, selective MMPs’ inhibitors might be potential targets for therapeutic strategies for patients with ALS. However, future investigations are necessary before some of those non-specific for ALS enzymes could finally be used as biomarkers of this disease

Clinical significance of serum levels of matrix metalloproteinase 2 (MMP-2) and its tissue inhibitor (TIMP-2) in gastric cancer

Matrix metalloproteinase 2 (MMP-2) is able to degrade type IV collagen, and thus plays a key role in the migration of tumor cells. MMP-2 activity is inhibited by its tissue inhibitor (TIMP-2). The imbalance between MMPs and TIMPs may facilitate progression of cancer cells. The aim of this study was to compare the clinical importance of MMP-2 and TIMP-2 to that of classical tumor markers, namely carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) in the diagnosis of gastric cancer (GC) by calculating the diagnostic criteria and estimating the levels of MMP-2, TIMP-2, CEA and CA 19-9 in GC patients in relation to clinicopathological features of cancer. We found that serum levels of MMP-2 and TIMP-2 were significantly lower, whereas serum tumor markers were higher, in GC patients than in healthy subjects. Moreover, concentrations of TIMP-2 and CEA correlated with gastric wall infiltration, while CA 19-9 levels correlated with gastric wall infiltration and the presence of nodal metastasis. None of the proteins tested was found to be an independent prognostic factor for GC patients’ survival. The percentage of true positive results of TIMP-2 (61%) was higher than those of MMP-2 (54%) and the classical tumor markers CEA (21%) and CA 19-9 (31%). The highest diagnostic sensitivity was observed for the combined use of TIMP-2 with MMP-2 (77%). The results suggest the greater importance of serum MMP-2 and TIMP-2 than of the classical tumor markers CEA and CA 19-9 in the diagnosis of GC. But this issue requires further investigation. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 1, pp. 125–131

The impact of laparoscopic adrenalectomy on renal function. Results of a prospective randomised clinical trial

Introduction: Laparoscopic adrenalectomy is the gold standard management of benign adrenal masses and isolated metastases to adrenal glands. Two techniques of endoscopic adrenalectomy: lateral transperitoneal approach (LTA) and posterior retroperitoneal approach (PRA) seem to be equally safe and effective. Recent studies suggest advantages of PRA over LTA in terms of lower intensity of postoperative pain, shorter hospital stay, faster recovery, and lower early morbidity. However, PRA involves high insufflation pressure of CO2 within a limited retroperitoneal space. The aim of our study was to prospectively assess the effect of LTA versus PRA laparoscopic adrenalectomies on renal function. Material and methods: We randomly assigned patients referred for unilateral adrenalectomy to either LTA (n = 33) or PRA (n = 44). The inclusion criteria were: hormonal activity and/or tumour diameter > 4 cm and/or suspicion of metastasis to adrenal gland. The exclusion criteria comprised: tumours > 8 cm, results of imaging studies suggesting primary invasive malignancy, and refusal to undergo randomisation. The patients were prospectively followed for a minimum of six months. Serum creatinine, cystatin C, and urinary neutrophil gelatinase-associated lipocalin (NGAL) were measured preoperatively and at postoperative days: 1, 7, and 30. Results: We found increased concentrations of urinary NGAL at day 1 following laparoscopic adrenalectomy using PRA, as compared to LTA. Patients undergoing right-sided PRA had increased creatinine concentrations, as compared to left-sided PRA. Patients with aldosterone-producing adenoma had decreased preoperative eGFR as compared to subjects with non-functioning incidentaloma. NGAL increased significantly in this group postoperatively. All the disturbances normalised within one month postoperatively. Conclusions: Renal function impairment after PRA may result from compression of inferior vena cava by high retroperitoneal pressure during right-sided adrenalectomy. Despite the transient character of the observed abnormalities, we suggest that patients with high risk of acute kidney injury may benefit from an alternative technique of adrenalectomy using LTA

Comparison between clinical significance of serum proinflammatory proteins (IL-6 and CRP) and classic tumor markers (CEA and CA 19-9) in gastric cancer

Gastric cancer (GC) is a second most common cause of cancer-related death and represents an inflammation-driven malignancy. It has been suggested that interleukin 6 (IL-6) and C-reactive protein (CRP) play a potential role in the growth and progression of GC. The aim of the present study was to compare clinical significance of IL-6 and CRP with classic tumor markers—carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) in GC patients. The study included 92 patients with GC and 70 healthy subjects. The serum concentrations of IL-6, CEA and CA 19-9 were determined using immunoenzyme assays, whereas CRP using immunoturbidimetric method. We defined the diagnostic criteria and prognostic value for proteins tested. In GC patients, the serum concentrations of all the proteins tested were significantly higher than in healthy subjects. The IL-6, CEA and CA 19-9 levels correlated with nodal metastases, while CRP with tumor stage, gastric wall invasion, presence of nodal and distant metastases. Diagnostic sensitivity of IL-6 was higher (85%) than those of other markers (CRP 66%, CA 19-9 34%, CEA 22%) and increased in combined use with CRP or CEA (88%). The area under ROC curve for IL-6 was larger than those of CRP and classic tumor markers (CEA and CA 19-9). None of the proteins tested was independent prognostic factor for the survival of GC patients. Our findings indicate better usefulness of serum proinflammatory proteins—IL-6 and CRP than classic tumor markers—CEA and CA 19-9 in the diagnosis of GC

Circulating Biomarkers of Colorectal Cancer (CRC)—Their Utility in Diagnosis and Prognosis

The global burden of colorectal cancer (CRC) is expected to increase, with 2.2 million new cases and 1.1 million annual deaths by 2030. Therefore, the establishment of novel biomarkers useful in the early diagnosis of CRC is of utmost importance. A number of publications have documented the significance of the overexpression of several specific proteins, such as inflammatory mediators, in CRC progression. However, little is known about the potential utility of these proteins as circulating blood tumor biomarkers of CRC. Therefore, in the present review we report the results of our previous original studies as well as the findings of other authors who investigated whether inflammatory mediators might be used as novel biomarkers in the diagnosis and prognosis of CRC. Our study revealed that among all of the tested proteins, serum M-CSF, CXCL-8, IL-6 and TIMP-1 have the greatest value in the diagnosis and progression of CRC. Serum TIMP-1 is useful in differentiating between CRC and colorectal adenomas, whereas M-CSF and CRP are independent prognostic factors for the survival of patients with CRC. This review confirms the promising significance of these proteins as circulating biomarkers for CRC. However, due to their non-specific nature, further validation of their sensitivity and specificity is required

A Disintegrin and Metalloproteinase (ADAM) Family: Their Significance in Malignant Tumors of the Central Nervous System (CNS)

Despite the considerable advances in diagnostic methods in medicine, central nervous system (CNS) tumors, particularly the most common ones—gliomas—remain incurable, with similar incidence rates and mortality. A growing body of literature has revealed that degradation of the extracellular matrix by matrix metalloproteinases (MMPs) might be involved in the pathogenesis of CNS tumors. However, the subfamily of MMPs, known as disintegrin and metalloproteinase (ADAM) proteins are unique due to both adhesive and proteolytic activities. The objective of our review is to present the role of ADAMs in CNS tumors, particularly their involvement in the development of malignant gliomas. Moreover, we focus on the diagnostic and prognostic significance of selected ADAMs in patients with these neoplasms. It has been proven that ADAM12, ADAMTS4 and 5 are implicated in the proliferation and invasion of glioma cells. In addition, ADAM8 and ADAM19 are correlated with the invasive activity of glioma cells and unfavorable survival, while ADAM9, -10 and -17 are associated with tumor grade and histological type of gliomas and can be used as prognostic factors. In conclusion, several ADAMs might serve as potential diagnostic and prognostic biomarkers as well as therapeutic targets for malignant CNS tumors. However, future research on ADAMs biology should be performed to elucidate new strategies for tumor diagnosis and treatment of patients with these malignancies

Granzymes—Their Role in Colorectal Cancer

Colorectal cancer (CRC) is among the most common malignancies worldwide. CRC is considered a heterogeneous disease due to various clinical symptoms, biological behaviours, and a variety of mutations. A number of studies demonstrate that as many as 50% of CRC patients have distant metastases at the time of diagnosis. However, despite the fact that social and medical awareness of CRC has increased in recent years and screening programmes have expanded, there is still an urgent need to find new diagnostic tools for early detection of CRC. The effectiveness of the currently used classical tumour markers in CRC diagnostics is very limited. Therefore, new proteins that play an important role in the formation and progression of CRC are being sought. A number of recent studies show the potential significance of granzymes (GZMs) in carcinogenesis. These proteins are released by cytotoxic lymphocytes, which protect the body against viral infection as well specific signalling pathways that ultimately lead to cell death. Some studies suggest a link between GZMs, particularly the expression of Granzyme A, and inflammation. This paper summarises the role of GZMs in CRC pathogenesis through their involvement in the inflammatory process. Therefore, it seems that GZMs could become the focus of research into new CRC biomarkers

A Disintegrin and Metalloproteinase (ADAM) Family—Novel Biomarkers of Selected Gastrointestinal (GI) Malignancies?

The global burden of gastrointestinal (GI) cancers is expected to increase. Therefore, it is vital that novel biomarkers useful for the early diagnosis of these malignancies are established. A growing body of data has linked secretion of proteolytic enzymes, such as metalloproteinases (MMPs), which destroy the extracellular matrix, to pathogenesis of GI tumours. A disintegrin and metalloproteinase (ADAM) proteins belong to the MMP family but have been proven to be unique due to both proteolytic and adhesive properties. Recent investigations have demonstrated that the expression of several ADAMs is upregulated in GI cancer cells. Thus, the objective of this review is to present current findings concerning the role of ADAMs in the pathogenesis of GI cancers, particularly their involvement in the development and progression of colorectal, pancreatic and gastric cancer. Furthermore, the prognostic significance of selected ADAMs in patients with GI tumours is also presented. It has been proven that ADAM8, 9, 10, 12, 15, 17 and 28 might stimulate the proliferation and invasion of GI malignancies and may be associated with unfavourable survival. In conclusion, this review confirms the role of selected ADAMs in the pathogenesis of the most common GI cancers and indicates their promising significance as potential prognostic biomarkers as well as therapeutic targets for GI malignancies. However, due to their non-specific nature, future research on ADAM biology should be performed to elucidate new strategies for the diagnosis of these common and deadly malignancies and treatment of patients with these diseases

Subfertility as Overlapping of Nutritional, Endocrine, Immune, and Cardiometabolic Dysregulations—A Study Focused on Biochemical Endophenotypes of Subfertile Couples

Subfertility is a global health issue, and as many as 30% of cases are attributed to unexplained reasons. A hypercaloric, high-fat diet stimulates the expansion of pro-inflammatory gut microbiota with a consequent rise in circulating lipopolysaccharides. Adverse gut microbiota remodeling can exacerbate insulin resistance, while sex and thyroid hormones may influence the variability in gut microbiota. This cross-sectional study included 150 participants and was designed to determine a biochemical, nutritional-related pattern that may distinguish subfertile from fertile individuals and couples. A panel of 28 biomarkers was assessed. Four biochemical phenotypes of unexplained subfertility were found, including two metabolic and two immune, when assessed using binary logistic regression models. Two phenotypes were distinguished in women: cardio-metabolic with atherogenic dyslipidemia (LowHDL-cholesterol: OR = 10.9; p Highanti-thyroid-peroxidase: OR = 5.5; p HighHOMA-IR: OR = 6.1; p HighIgE: OR = 6.4; p p 100 kU/L) (OR = 6.5; p < 0.05). This study found that unexplained subfertility may be accompanied by mutually overlapping immune and metabolic dysregulations in individuals and couples. We propose one-time laboratory diagnostics taking into account the lipid profile, insulin resistance, anti-thyroid-peroxidase, and total IgE in both males and females with unexplained subfertility. This may allow for a one-time assessment of targeted medical and nutritional interventions and help optimize patients’ health. The gut–organ axes related to subfertility are discussed in the context of the obtained results