The Genetic Background of Abnormalities in Metabolic Pathways of Phosphoinositides and Their Linkage with the Myotubular Myopathies, Neurodegenerative Disorders, and Carcinogenesis.

Myo-inositol belongs to one of the sugar alcohol groups known as cyclitols. Phosphatidylinositols are one of the derivatives of Myo-inositol, and constitute important mediators in many intracellular processes such as cell growth, cell differentiation, receptor recycling, cytoskeletal organization, and membrane fusion. They also have even more functions that are essential for cell survival. Mutations in genes encoding phosphatidylinositols and their derivatives can lead to many disorders. This review aims to perform an in-depth analysis of these connections. Many authors emphasize the significant influence of phosphatidylinositols and phosphatidylinositols' phosphates in the pathogenesis of myotubular myopathies, neurodegenerative disorders, carcinogenesis, and other less frequently observed diseases. In our review, we have focused on three of the most often mentioned groups of disorders. Inositols are the topic of many studies, and yet, there are no clear results of successful clinical trials. Analysis of the available literature gives promising results and shows that further research is still needed.

Novel insights into the nervous system affected by prolonged hyperglycemia.

Multiple molecular pathways including the receptor for advanced glycation end-products-diaphanous related formin 1 (RAGE-Diaph1) signaling are known to play a role in diabetic peripheral neuropathy (DPN). Evidence suggests that neuropathological alterations in type 1 diabetic spinal cord may occur at the same time as or following peripheral nerve abnormalities. We demonstrated that DPN was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. More than 500 differentially expressed genes (DEGs) belonging to multiple functional pathways were identified in diabetic spinal cord and of those the most enriched was RAGE-Diaph1 related PI3K-Akt pathway. Only seven of spinal cord DEGs overlapped with DEGs from type 1 diabetic sciatic nerve and only a single gene cathepsin E (CTSE) was common for both type 1 and type 2 diabetic mice. In silico analysis suggests that molecular changes in spinal cord may act synergistically with RAGE-Diaph1 signaling axis in the peripheral nerve. KEY MESSAGES: Molecular perturbations in spinal cord may be involved in the progression of diabetic peripheral neuropathy. Diabetic peripheral neuropathy was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. In silico analysis revealed that PI3K-Akt signaling axis related to RAGE-Diaph1 was the most enriched biological pathway in diabetic spinal cord. Cathepsin E may be the target molecular hub for intervention against diabetic peripheral neuropathy.

The Current State of Osteoarthritis Treatment Options Using Stem Cells for Regenerative Therapy: A Review.

Articular cartilage has very low metabolic activity. While minor injuries may be spontaneously repaired within the joint by chondrocytes, there is very little chance of a severely impaired joint regenerating itself when damaged. Therefore, any significant joint injury has little chance of spontaneously healing without some type of therapy. This article is a review that will examine the causes of osteoarthritis, both acute and chronic, and how it may be treated using traditional methods as well as with the latest stem cell technology. The latest regenerative therapy is discussed, including the use and potential risks of mesenchymal stem cells for tissue regeneration and implantation. Applications are then discussed for the treatment of OA in humans after using canine animal models. Since the most successful research models of OA were dogs, the first applications for treatment were veterinary. However, the treatment options have now advanced to the point where patients suffering from osteoarthritis may be treated with this technology. A survey of the literature was performed in order to determine the current state of stem cell technology being used in the treatment of osteoarthritis. Then, the stem cell technology was compared with traditional treatment options.

Changes in the Neurochemical Characterization of Enteric Neurons in the Porcine Duodenum After Administration of Low-Dose Salmonella Enteritidis Lipopolysaccharides.

Lipopolysaccharides (LPS), also known as lipoglycans or endotoxins, form part of the outer membrane of Gram-negative bacteria. Previous studies have described the various harmful impacts of LPS on humans and animals. Nevertheless, many aspects of these effects are still not fully explained. One of them is the influence of endotoxins on the neurochemical characterization of neurons within the enteric nervous system (ENS), which is found in the intestinal wall and plays important adaptive roles during pathological processes and exposures. In this study, the impact of a low single dose of Salmonella Enteritidis LPS on the duodenal enteric neurons immunoreactive to substance P (SP), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase activating peptide (PACAP-27), and cocaine- and amphetamine-regulated transcript (CART) was studied using a double immunofluorescence technique. During the study, it was shown that even a low dose of LPS affects the number of enteric neurons containing the neuropeptides studied, and these changes were dependent on the type of the enteric plexus. The most visible changes concerned the SP-like immunoreactive (LI) neurons in the outer submucous plexus (LPS caused an increase in the percentage of these neurons from15.74 ± 0.61 to 21.72 ± 0.79%). Furthermore, the VIP-LI neurons in the inner submucous plexus were seen to decrease from 12.64 ± 0.83 to 5.96 ± 0.58%. The mechanisms behind these noted fluctuations are not clear, but it may be connected with the pro-inflammatory and neurotoxic activity of LPS.

Cancer Prevention by Natural Products Introduced into the Diet-Selected Cyclitols.

Cancer is now the second leading cause of death worldwide. It is estimated that every year, approximately 9.6 million people die of oncologic diseases. The most common origins of malignancy are the lungs, breasts, and colorectum. Even though in recent years, many new drugs and therapeutic options have been introduced, there are still no safe, effective chemopreventive agents. Cyclitols seem poised to improve this situation. There is a body of evidence that suggests that their supplementation can decrease the incidence of colorectal cancer, lower the risk of metastasis occurrence, lower the proliferation index, induce apoptosis in malignant cells, enhance natural killer (NK) cell activity, protect cells from free radical damage, and induce positive molecular changes, as well as reduce the side effects of anticancer treatments such as chemotherapy or surgery. Cyclitol supplementation appears to be both safe and well-tolerated. This review focuses on presenting, in a comprehensive way, the currently available knowledge regarding the use of cyclitols in the treatment of different malignancies, particularly in lung, breast, colorectal, and prostate cancers.

Differentiation of Human Mesenchymal Stem Cells from Wharton's Jelly Towards Neural Stem Cells Using A Feasible and Repeatable Protocol.

The transplantation of neural stem cells (NSCs) capable of regenerating to the cells of the central nervous system (CNS) is a promising strategy in the treatment of CNS diseases and injury. As previous studies have highlighted mesenchymal stem cells (MSCs) as a source of NSCs, this study aimed to develop a feasible, efficient, and reproducible method for the neural induction of MSCs isolated from Wharton's jelly (hWJ-MSCs). We induced neural differentiation in a monolayer culture using epidermal growth factor, basic fibroblast growth factor, N2, and B27 supplements. This resulted in a homogenous population of proliferating cells that expressed certain neural markers at both the protein and mRNA levels. Flow cytometry and immunocytochemistry confirmed the expression of neural markers: nestin, sex-determining region Y (SRY) box 1 and 2 (SOX1 and SOX2), microtubule-associated protein 2 (MAP2), and glial fibrillary acidic protein (GFAP). The qRT-PCR analysis revealed significantly enhanced expression of nestin and MAP2 in differentiated cells. This study confirms that it is possible to generate NSCs-like cells from hWJ-MSCs in a 2D culture using a practical method. However, the therapeutic effectiveness of such differentiated cells should be extended to confirm the terminal differentiation ability and electrophysiological properties of neurons derived from them.

Bisphenol S in Food Causes Hormonal and Obesogenic Effects Comparable to or Worse than Bisphenol A: A Literature Review.

In recent years, bisphenol analogues such as bisphenol S (BPS) have come to replace bisphenol A in food packaging and food containers, since bisphenol A (BPA) has been shown to leach into food and water, causing numerous negative health effects. Unfortunately, little or no research was done to determine the safety of these BPA-free products before they were marketed to the public as a healthier alternative. The latest studies have shown that some of these bisphenol analogues may be even more harmful than the original BPA in some situations. This article used a literature survey to investigate the bisphenol analogue BPS and compare it to BPA and other analogues with regards to increased obesity, metabolic disorders, cancer, and reproductive defects; among others. It was found that BPS works via different pathways than does BPA while causing equivalent obesogenic effects, such as activating preadipocytes, and that BPS was correlated with metabolic disorders, such as gestational diabetes, that BPA was not correlated with. BPS was also shown to be more toxic to the reproductive system than BPA and was shown to hormonally promote certain breast cancers at the same rate as BPA. Therefore, a strong argument may be made to regulate BPS in exactly the same manner as BPA.

Inositols' Importance in the Improvement of the Endocrine-Metabolic Profile in PCOS.

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility and metabolic problems among women of reproductive age. The mechanism of PCOS is associated with concurrent alterations at the hormonal level. The diagnosis assumes the occurrence of three interrelated symptoms of varying severity, namely ovulation disorders, androgen excess, or polycystic ovarian morphology (PCOM), which all require a proper therapeutic approach. The main symptom seems to be an increased androgen concentration, which in turn may contribute to different metabolic disorders. A number of papers have demonstrated the significant role of inositol therapy in PCOS. However, there is a lack of detailed discussion about the importance of myo-inositol (MI) and d-chiro-inositol (DCI) in reference to particular symptoms. Thus, the aim of this review is to present the effectiveness of MI and DCI treatment for PCOS symptoms. Moreover, the review is focused on analyzing the use of inositols, taking into account their physiological properties, together with the mechanism of individual PCOS symptom formation.

Role of Microparticles in the Pathogenesis of Inflammatory Joint Diseases.

Rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) make up a group of chronic immune-mediated inflammatory diseases (IMIDs). The course of these diseases involves chronic inflammation of joints and enthesopathies, which can result in joint damage and disability. Microparticles (MPs) are a group of small spherical membranous vesicles. The structure and cellular origin of MPs, mechanisms that stimulate their secretion and the place of their production, determine their biological properties, which could become manifest in the pathogenesis of immune-mediated inflammatory diseases. Microparticles can stimulate synovitis with proinflammatory cytokines and chemokines. MPs may also contribute to the pathogenesis of rheumatic diseases by the formation of immune complexes and complement activation, pro-coagulation activity, activation of vascular endothelium cells, and stimulation of metalloproteinase production. It seems that in the future, microparticles can become a modern marker of disease activity, a response to treatment, and, possibly, they can be used in the prognosis of the course of arthritis. The knowledge of the complexity of MPs biology remains incomplete and it requires further comprehensive studies to explain how they affect the development of rheumatic diseases. This review focuses on the immunopathogenic and therapeutic role of MPs in chronic immune-mediated inflammatory joint diseases.

Review of the Current Knowledge on the Role of Stem Cell Transplantation in Neurorehabilitation.

The management involving stem cell (SC) therapy along with physiotherapy offers tremendous chance for patients after spinal cord injury (SCI), traumatic brain injury (TBI), stroke, etc. However, there are still only a limited number of reports assessing the impact of stem cells (SCs) on the rehabilitation process and/or the results of the simultaneous use of SC and rehabilitation. Additionally, since there is still not enough convincing evidence about the effect of SCT on humans, e.g., in stroke, there have been no studies conducted concerning rehabilitation program formation and expected outcomes. It has been shown that bone marrow-derived mesenchymal stem cell (BMSCs) transplantation in rats combined with hyperbaric oxygen therapy (HBO) can promote the functional recovery of hind limbs after SCI. An anti-inflammatory effect has been shown. One case study showed that, after the simultaneous use of SCT and rehabilitation, an SCI patient progressed from ASIA Grade A to ASIA Grade C. Such promising data in the case of complete tetraplegia could be a breakthrough in the treatment of neurologic disorders in humans. Although SCT appears as a promising method for the treatment of neurological conditions, e.g., complete tetraplegia, much work should be done towards the development of rehabilitation protocols.

Distal interphalangeal joint extensor tendon enthesopathy in patients with nail psoriasis.

The aim of the study was an ultrasound assessment of distal interphalangeal (DIP) joint enthesopathy in patients with nail psoriasis. Altogether, 72 patients with nail psoriasis (41 with psoriasis and 31 with psoriatic arthritis) and 30 people in the control group participated in the study. In total, 1014 nails were examined. The thickness of DIP digital extensor tendons in the groups of patients with psoriasis (Ps) and psoriatic arthritis (PsA) was correlated with the nail bed thickness (r = 0.316, p = 0.027 vs. r = 0.402, p = 0.031, respectively) and with the thickness of the nail matrix in patients with psoriasis (r = 0.421, p = 0.012). The linear regression model showed the tendon thickness in Ps patients to be affected by the nail bed thickness, duration of psoriasis and the thickness of the nail matrix, whereas in PsA patients it was found to be significantly affected by duration of psoriasis and of arthritis, the nail bed thickness, CRP concentration and the swollen joint count. Our findings may indicate the role of the nail-tendon apparatus changes in the PsA development and they emphasise the justifiability of US examinations in patients with psoriasis direct assessment of morphological changes in nails as potential predictors of PsA development.

COMPLEX TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS PATIENT.

Amyotrophic lateral sclerosis is a progressive and fatal degenerative neuromuscular disease with few if any treatment options and physical rehabilitation addressing specific deficits is the most frequent form of therapy. Patients also suffer from depression and increased anxiety. Our purpose was to assess the neurorehabilitation effectiveness in a patient with amyotrophic lateral sclerosis who underwent stem cell transplantation but refused physiotherapy due to depression. Disease progression was followed using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale bimonthly for six months pre- and then post-stem cell transplantation. Psychological traits were assessed using six standardized tests. Quantitative electroencephalogram diagnostics was performed before the first and after the last neurofeedback session, and sessions were conducted on a 3-times-a-week basis. The physiotherapy protocol included proprioceptive neuromuscular facilitation, electrical modalities unit applied to the lumbar spine area, and breathing, relaxation and walking exercises, among others. Increased motivation and marked decrease in the pain level was associated with the patient's willingness to complete physiotherapy, which resulted in improvements in most neuromuscular deficits and in increased respiratory capacity. During the 12 post-rehabilitation months, progression of the disease decelerated, and a positive behavioral change was noted. The study suggested that neurofeedback could be used as a neurorehabilitation component of the personalized complex rehabilitation protocol in patients with amyotrophic lateral sclerosis.

Effect of Methotrexate in the Treatment of Distal Interphalangeal Joint Extensor Tendon Enthesopathy in Patients with Nail Psoriasis.

To assess the effect of methotrexate on the development of distal interphalangeal joint extensor tendon enthesopathy in psoriasis, thirty-two people aged 34 to 57 years with nail psoriasis and distal interphalangeal joint extensor tendon enthesopathy (19 patients with Ps (psoriasis) and 13 with PsA (psoriatic arthritis) were started on methotrexate at 15 to 25 mg/week and the treatment was continued for 6 months). A total of 319 nails were examined. After six months of treatment, the thicknesses of the nail plate, nail bed and nail matrix were found to decrease in both groups of patients. Methotrexate treatment resulted in a decrease in the joint extensor tendon thickness only in patients with Ps (0.94 ± 0.05 vs. 0.96 ± 0.04, p < 0.001), where the tendon thickness after treatment correlated with the matrix thickness (r = 0.337, p = 0.018) and with the bed thickness (r = 0.299, p = 0.039). Methotrexate treatment resulted in a decrease in the extensor tendon thickness only in patients with Ps but not in PsA. The findings of this study may suggest the effectiveness of systemic treatment of nail psoriasis in patients without arthritis and the use of US nail examinations in Ps and PsA patients in morphological change assessment and response to treatment.

Evaluation of regenerative processes in the pig model of intervertebral disc degeneration after transplantation of bone marrow-derived mesenchymal stem cells.

INTRODUCTION: The pathophysiology of degenerative disc disease (DDD) is complex and not fully understood. While surgical treatment and appropriate rehabilitation offer relief of acute symptoms, there is a need to find tissue engineering strategies for intervertebral disc repair to restore healthy higher and histological structure. The purpose of this study was to estimate the survival rate of transplanted cells and their post-delivery integration level at the damage site. MATERIAL AND METHODS: We used an in vivo porcine model to investigate autogenic bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation for intervertebral disc repair. In our experiment we used a large animal model of DDD induced by percutaneous laser light deliveries. The percutaneous approach has also been used for delivery of BM-MSCs into the intervertebral disc space. RESULTS: After MSC transplantation, we observed a deceleration of the degenerative process in the intervertebral disc, relative to degenerative discs without MSC transplantation. CONCLUSIONS: By using a large animal model that mimicked the development of intervertebral degenerative disc disease, the present results are indicative of the clinical feasibility of this procedure.

Ultrasound Assessment of Changes in Nails in Psoriasis and Psoriatic Arthritis.

AIM OF THE STUDY: The aim of the study was to conduct an ultrasound (US) assessment of changes in fingernails in psoriatic patients with nail involvement. MATERIAL: A total of 69 patients with psoriatic changes in nails participated in the study, including 38 patients with psoriasis (Ps) and 31 with psoriatic arthritis (PsA) and 30 people in the control group. A total of 988 nails were examined. RESULTS: The thickness of the nail plate, nail bed, and matrix as shown in an ultrasound examination increased with the mNAPSI index (r=0.328, p=0.021; r=0.219, p=0.036; and r=0.422, p=0.011, respectively). The thickness of nail plate, bed, and matrix in patients with onycholysis and hyperkeratosis-type changes (concomitant or present separately) was significantly greater than when only pitting-type changes occurred (p=0.007, p=0.035, and p=0.023, respectively). An examination of nails with only pitting-type changes showed an increase in the matrix thickness compared to the control group (p=0.018). The focal hyperechoic involvement of the dorsal plate (80%) was the change most often observed in an US examination in Ps patients, whereas loosening of the borders of the ventral plate was most often observed in PsA patients. The thickness of nail bed in PsA patients increased with the duration of arthritis (r=0.399, p=0.022) and was correlated with the number of swollen digits (r=0.278, p=0.041). CONCLUSIONS: The findings of this study may indicate an association of an inflammation in the nail bed with PsA development. Apart from a direct assessment of the described morphological changes of nails, a US examination could prove useful in an assessment of intensity of a local inflammation as a prognostic factor for PsA development.

Neurochemical characterization of intramural nerve fibres in the porcine oesophagus.

The gastrointestinal (GI) tract is innervated by nerve processes derived from the intramural enteric neurons and neurons localized outside the digestive tract. This study analysed the neurochemical characterization of nerves in the wall of the porcine oesophagus using single immunofluorescence technique. Immunoreactivity to vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), galanin (GAL), neuronal isoform of nitric oxide synthase (nNOS), substance P (SP), leucine enkephalin (LENK), calcitonin gene-related peptide (CGRP) or dopamine beta-hydroxylase (DBH) was investigated in intramuscular and intramucosal nerves of the cervical, thoracic and abdominal oesophagus. The results indicate that all of the substances studied were present in the oesophageal nerves. The density of particular populations of fibres depended on the segment of the oesophagus. The most numerous were fibres immunoreactive to VIP in the longitudinal and circular muscle layers of the abdominal oesophagus: The number of these fibres amounted to 16.4 ± 0.8 and 18.1 ± 3.1, respectively. In turn, the least numerous were CGRP-positive fibres, which were present only in the circular muscle layer of the cervical oesophagus and mucosal layer of the abdominal oesophagus in the number of 0.3 ± 0. The obtained results show that nerves in the porcine oesophageal wall are very diverse in their neurochemical coding, and differences between particular parts of the oesophagus suggest that organization of the innervation clearly depends on the fragment of this organ.

Application of MRI for the Diagnosis of Neoplasms.

AIM: The aim of the study was to determine the most commonly diagnosed neoplasms in the MRI scanned patient population and indicate correlations based on the descriptive variables. METHODS: The SPSS software was used to determine the incidence of neoplasms within the specific diagnoses based on the descriptive variables of the studied population. Over a five year period, 791 patients and 839 MRI scans were identified in neoplasm category (C00-D48 according to the International Statistical Classification of Diseases and Related Health Problems ICD-10). RESULTS: More women (56%) than men (44%) represented C00-D48. Three categories of neoplasms were recorded. Furthermore, benign neoplasms were the most numerous, diagnosed mainly in patients in the fifth decade of life, and included benign neoplasms of the brain and other parts of the central nervous system. CONCLUSIONS: Males ≤ 30 years of age with neoplasms had three times higher MRI scans rate than females of the same age group; even though females had much higher scans rate in every other category. The young males are more often selected for these scans if a neoplasm is suspected. Finally, the number of MRI-diagnosed neoplasms showed a linear annual increase.

Articular Cartilage Aging-Potential Regenerative Capacities of Cell Manipulation and Stem Cell Therapy.

Changes in articular cartilage during the aging process are a stage of natural changes in the human body. Old age is the major risk factor for osteoarthritis but the disease does not have to be an inevitable consequence of aging. Chondrocytes are particularly prone to developing age-related changes. Changes in articular cartilage that take place in the course of aging include the acquisition of the senescence-associated secretory phenotype by chondrocytes, a decrease in the sensitivity of chondrocytes to growth factors, a destructive effect of chronic production of reactive oxygen species and the accumulation of the glycation end products. All of these factors affect the mechanical properties of articular cartilage. A better understanding of the underlying mechanisms in the process of articular cartilage aging may help to create new therapies aimed at slowing or inhibiting age-related modifications of articular cartilage. This paper presents the causes and consequences of cellular aging of chondrocytes and the biological therapeutic outlook for the regeneration of age-related changes of articular cartilage.

Role of Stem Cells in Pathophysiology and Therapy of Spondyloarthropathies-New Therapeutic Possibilities?

Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-α, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Although they adequately control inflammatory symptoms, they do not affect the abnormal bone formation processes associated with SpA. However, the traditional therapeutic approach does not cover the regenerative treatment of damaged tissues. In this regards, stem cells may offer a promising, safe and effective therapeutic option. The aim of this paper is to present the role of mesenchymal stromal cells (MSC) in pathogenesis of SpA and to highlight the opportunities for using stem cells in regenerative processes and in the treatment of inflammatory changes in articular structures.

Can Youthful Mesenchymal Stem Cells from Wharton's Jelly Bring a Breath of Fresh Air for COPD?

Chronic obstructive pulmonary disease (COPD) is a major global cause of morbidity and mortality, projected to become the 3rd cause of disease mortality worldwide by 2020. COPD is characterized by persistent and not fully reversible airflow limitation that is usually progressive and is associated with an abnormal chronic inflammatory response of the lung to noxious agents including cigarette smoke. Currently available therapeutic strategies aim to ease COPD symptoms but cannot prevent its progress or regenerate physiological lung structure or function. The urgently needed new approaches for the treatment of COPD include stem cell therapies among which transplantation of mesenchymal stem cells derived from Wharton's jelly (WJ-MSCs) emerges as a promising therapeutic strategy because of the unique properties of these cells. The present review discusses the main biological properties of WJ-MSCs pertinent to their potential application for the treatment of COPD in the context of COPD pathomechanisms with emphasis on chronic immune inflammatory processes that play key roles in the development and progression of COPD.