Salidroside: A Promising Agent in Bone Metabolism Modulation.

Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key regulatory proteins including runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone development with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2-related factor 2 pathway. Salidroside has the capability to counteract the negative effects of glucocorticoids on bone cells and prevents steroid-induced osteonecrosis. Additionally, it exhibits multifaceted anti-inflammatory actions, notably through the inhibition of tumor necrosis factor-alpha and interleukin-6 expression, while enhancing the expression of interleukin-10. This publication presents a comprehensive review of the literature on the impact of salidroside on various aspects of bone tissue metabolism, emphasizing its potential role in the prevention and treatment of osteoporosis and other diseases affecting bone physiology.

The Role of Rosavin in the Pathophysiology of Bone Metabolism.

Rosavin, a phenylpropanoid in Rhodiola rosea's rhizome, and an adaptogen, is known for enhancing the body's response to environmental stress. It significantly affects cellular metabolism in health and many diseases, particularly influencing bone tissue metabolism. In vitro, rosavin inhibits osteoclastogenesis, disrupts F-actin ring formation, and reduces the expression of osteoclastogenesis-related genes such as cathepsin K, calcitonin receptor (CTR), tumor necrosis factor receptor-associated factor 6 (TRAF6), tartrate-resistant acid phosphatase (TRAP), and matrix metallopeptidase 9 (MMP-9). It also impedes the nuclear factor of activated T-cell cytoplasmic 1 (NFATc1), c-Fos, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways and blocks phosphorylation processes crucial for bone resorption. Moreover, rosavin promotes osteogenesis and osteoblast differentiation and increases mouse runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) expression. In vivo studies show its effectiveness in enhancing bone mineral density (BMD) in postmenopausal osteoporosis (PMOP) mice, restraining osteoclast maturation, and increasing the active osteoblast percentage in bone tissue. It modulates mRNA expressions by increasing eukaryotic translation elongation factor 2 (EEF2) and decreasing histone deacetylase 1 (HDAC1), thereby activating osteoprotective epigenetic mechanisms, and alters many serum markers, including decreasing cross-linked C-telopeptide of type I collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator for nuclear factor κ B ligand (RANKL), macrophage-colony-stimulating factor (M-CSF), and TRAP, while increasing alkaline phosphatase (ALP) and OCN. Additionally, when combined with zinc and probiotics, it reduces pro-osteoporotic matrix metallopeptidase 3 (MMP-3), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), and enhances anti-osteoporotic interleukin 10 (IL-10) and tissue inhibitor of metalloproteinase 3 (TIMP3) expressions. This paper aims to systematically review rosavin's impact on bone tissue metabolism, exploring its potential in osteoporosis prevention and treatment, and suggesting future research directions.

The Role of Progranulin (PGRN) in the Pathogenesis of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) represents the most common and aggressive malignant form of brain tumour in adults and is characterized by an extremely poor prognosis with dismal survival rates. Currently, expanding concepts concerning the pathophysiology of GBM are inextricably linked with neuroinflammatory phenomena. On account of this fact, the identification of novel pathomechanisms targeting neuroinflammation seems to be crucial in terms of yielding successful individual therapeutic strategies. In recent years, the pleiotropic growth factor progranulin (PGRN) has attracted significant attention in the neuroscience and oncological community regarding its neuroimmunomodulatory and oncogenic functions. This review of the literature summarizes and updates contemporary knowledge about PGRN, its associated receptors and signalling pathway involvement in GBM pathogenesis, indicating possible cellular and molecular mechanisms with potential diagnostic, prognostic and therapeutic targets in order to yield successful individual therapeutic strategies. After a review of the literature, we found that there are possible PGRN-targeted therapeutic approaches for implementation in GBM treatment algorithms both in preclinical and future clinical studies. Furthermore, PGRN-targeted therapies exerted their highest efficacy in combination with other established chemotherapeutic agents, such as temozolomide. The results of the analysis suggested that the possible implementation of routine determinations of PGRN and its associated receptors in tumour tissue and biofluids could serve as a diagnostic and prognostic biomarker of GBM. Furthermore, promising preclinical applications of PGRN-related findings should be investigated in clinical studies in order to create new diagnostic and therapeutic algorithms for GBM treatment.

Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence.

Coronavirus disease 2019 (COVID-19), a pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can affect almost all systems and organs of the human body, including those responsible for reproductive function in women. The multisystem inflammatory response in COVID-19 shows many analogies with mast cell activation syndrome (MCAS), and MCAS may be an important component in the course of COVID-19. Of note, the female sex hormones estradiol (E2) and progesterone (P4) significantly influence mast cell (MC) behavior. This review presents the importance of MCs and the mediators from their granules in the female reproductive system, including pregnancy, and discusses the mechanism of potential disorders related to MCAS. Then, the available data on COVID-19 in the context of hormonal disorders, the course of endometriosis, female fertility, and the course of pregnancy were compiled to verify intuitively predicted threats. Surprisingly, although COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in MCAS, the available clinical data do not provide grounds for treating this mechanism as significantly increasing the risk of abnormal female reproductive function, including pregnancy. Further studies in the context of post COVID-19 condition (long COVID), where inflammation and a procoagulative state resemble many aspects of MCAS, are needed.

The role of inflammatory mediators in the pathogenesis of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome.

INTRODUCTION: As a recurrent disease, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is characterized by episodes of febrile attacks and is often prominent in children under five years of age. However, the etiology of this condition has not been fully understood yet. MATERIALS AND METHODS: The search in the extensive literature of peer-reviewed articles published from the inception to December 2021 was conducted to identify the relevant studies, using the electronic databases of MEDLINE/PubMed, Embase, Scopus, the Cochrane Library, and the Web of Science. RESULTS: The analysis of complex relationships indicates that inflammatory factors, such as various cytokines and acute-phase proteins (APPs), play leading roles in the pathogenesis of this disease. Accordingly, this article summarizes the current state of knowledge to explain the mechanisms involved in inflammatory responses among patients with PFAPA syndrome and investigate its role in the pathogenesis of this disease. Moreover, the possibilities for further implementation of new therapeutic strategies are pointed out. CONCLUSION: It is concluded that some pathophysiological processes are associated with immune dysregulation, which itself may be secondary to environmental factors, genetic background, and underlying diseases, including latent infections that multiply inflammatory mediators. elevated inflammatory markers similarly play a significant part in the clinical outcomes of this condition, whose pyrogenic nature is the reason for the development of episodes of febrile attacks in the population of patients suffering from PFAPA syndrome.

Involvement of progranulin (PGRN) in the pathogenesis and prognosis of breast cancer.

Breast cancer constitute a common type of oncological disease with a highlighted mortality rate. In recent years, researchers have introduced progranulin (PGRN) as an novel potential biomarker and associated its function with higher risk factor for development of breast cancer. The present review article collects evidence on the association of PGRN with clinicopathological features and drug resistance in the patients with breast cancer. The results of this study suggested the use of routine determination of PGRN in the clinic as a reliable biomarker for screening people at high risk or as early indication of breast cancer. Targeting PGRN and its associated signaling pathways and receptors, such as sortilin (SORT1), could also cover a novel therapeutic strategy in the breast cancer.

The Role of TNF-α and Anti-TNF-α Agents during Preconception, Pregnancy, and Breastfeeding.

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.

Comparative Analysis of the Occurrence and Role of CX3CL1 (Fractalkine) and Its Receptor CX3CR1 in Hemophilic Arthropathy and Osteoarthritis.

OBJECTIVE: Hemophilic arthropathy is characterized by recurrent bleeding episodes in patients with hemophilia leading to irreversible joint degeneration. The involvement of CX3CL1 (fractalkine) and its receptor CX3CR1 was observed in the pathogenesis of numerous arthritis-associated diseases. Taking this into account, we have presented a study investigating the role of the CX3CL1/CX3XR1 axis in the course of hemophilic arthropathy, including the CX3CL1-dependent expression of CD56+, CD68+, and CD31+ cells along with evaluation of articular cartilage and synovial membrane morphology. METHODS: The study was carried out using cases (n = 20) of end-stage hemophilic arthropathy with a severe type of hemophilia A and control cases (n = 20) diagnosed with osteoarthritis. The biofluids including blood serum and synovial fluid were obtained intraoperatively for the evaluation of CX3CL1 using the ELISA test. Tissue specimens including articular cartilage and synovial membrane were similarly collected during surgery and stained immunohistologically using selected antibodies including anti-CX3CR1, anti-CD56, anti-CD68, and anti-CD31. Additionally, the analysis included the assessment of articular cartilage, synovial membrane, and blood vessel morphology. RESULTS: In our study, we have documented increased average concentration of CX3CL1 in the blood serum of the study group (7.16 ± 0.53 ng/ml) compared to the control group (5.85 ± 0.70 ng/ml) without statistically significant difference in synovial fluid concentration at the same time. We have observed an increased macrophage presence with more marked proliferation and fibrosis of the synovial membrane in the study group. Remaining results such as expression of CX3CR1 presence of NK cells and larger surface area of blood vessels within the synovial membrane were noted also without statistical significance. CONCLUSIONS: This study has demonstrated collective CX3CL1/CX3CR1 axis involvement in hemophilic arthropathy pathogenesis introducing new interesting diagnostics and a therapeutic target.

IL-35, TNF-α, BAFF, and VEGF serum levels in patients with different rheumatic diseases.

OBJECTIVES: Inflammatory processes in rheumatic diseases spread via various types of immune system cells and tissues with the aid of inflammatory cytokines and growth factors and the participation of vascular endothelium. Research is still conducted to determine the role of individual factors in the pathophysiology of rheumatic diseases. The task is complicated because the multiplane network of cytokines is characterized by complex correlations manifesting as positive and negative feedback, which impedes the definitive interpretation of the role of specific cytokines. Therefore, it seems justified to perform a comparative analysis of the expression of at least several molecules in one study, which may help reveal their role in the pathogenesis of rheumatic diseases and have prognostic value. MATERIAL AND METHODS: The aim of the study involves the assessment and comparative analysis of the concentrations of interleukin 35 (IL-35), tumour necrosis factor α (TNF-α), B-cell-activating factor (BAFF), and vascular endothelial growth factor (VEGF) in peripheral blood serum in patients with rheumatoid arthritis (RA) (n = 43), systemic lupus erythematosus (SLE) (n = 28), antiphospholipid syndrome (APS) (n = 24), and mixed connective tissue disease (MCTD) (n = 9). The main intention is to search for biomarkers for specific rheumatic diseases. Cytokine and growth factor levels were determined using specific ELISA kits. RESULTS: Statistically significant differences in VEGF and IL-35 concentrations occurred between patients with APS vs. RA and SLE vs. RA. There was a significant high positive correlation between the concentration of BAFF and TNF-α (r = 0.77, p < 0.0000) in patients with APS, as well as in patients with SLE (r = 0.55, p = 0.00). CONCLUSIONS: BAFF and TNF-α may be promising biomarkers in patients with APS and VEGF in patients with RA. Additionally, IL-35 may be a useful marker for the diagnosis of APS. Positive correlation of BAFF and TNF-α concentrations in APS and SLE potentially indicates much more similar etiopathogenesis of these diseases than it could be previously predicted.

Cytokines in the pathogenesis of hemophilic arthropathy.

Hemophilic arthropathy (HA) is one of the most common and typical manifestation in the course of recurrent bleeding episodes in patients with hemophilia. Clinical and subclinical joint bleeding episodes gradually lead to irreversible changes manifesting themselves as pain, progressing ankylosis, marked limitation of the range of motion, muscle atrophy and osteoporosis commonly concomitant with joint deformity resulting from chronic proliferative synovitis and both cartilage and bone degeneration leading to the final functional impairment of the joint. In spite of numerous studies, the pathophysiology of HA has not been fully elucidated, especially as regards immunopathological mechanisms which are associated with the subclinical and early stage of the disease and to be more precise, with chronic joint inflammation. It needs to be emphasized that the pathophysiological processes occurring in a joint with HA are most probably highly mediated by interactions within the cytokine network and other inflammatory mediators present in the tissues of affected joint. Among numerous compounds participating in the induction of an inflammatory process in the pathogenesis of HA, cytokines seem to play a leading role. The most important group controlling the disease seems to be well known inflammatory cytokines, including IL-1ß, TNFα and IL-6. The second group with antagonistic effect is formed by anti-inflammatory cytokines such as IL-4 and IL-10. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of HA with respect to cellular and intracellular signaling pathways is still under investigation. This review, summarizes and discusses the current knowledge about cytokine network in the pathogenesis of HA, indicating possible molecular and cellular mechanisms that may provide potential new therapeutic directions.

Discrepancies in assessment of patients with rheumatoid arthritis and secondary Sjögren's syndrome by DAS28-ESR and DAS28-CRP.

OBJECTIVES: To investigate whether a difference exists between DAS28 from CRP and DAS28 from ESR in patients with rheumatoid arthritis (RA) and secondary Sjögren's syndrome (sSS). MATERIAL AND METHODS: One group comprised patients with RA and sSS, the control group comprised patients with RA. The inclusion criteria for the RA and sSS group have been specified as follows: presence of at least one symptom of dryness, and also presence of anti-SS-A and anti-SS-B or at least focus score of one in biopsy. RESULTS: The disease activity score 28 (DAS28) was assessed using both ESR and CRP in 60 patients with RA and sSS and 59 patients with RA alone. However, concordance between these two methods was good (Cohen's κ coefficient κ = 0.60, 95% CI: 0.45-0.75 in the first group and κ = 0.71, 95% CI: 0.56-0.86 in the control group). In the group with RA and sSS, the mean value of DAS28-ESR = 5.2, whereas the mean value of DAS28-CRP = 4.7 (p < 0.0001). In the group with RA alone, mean DAS28-ESR = 4.7 while mean DAS28-CRP = 4.6; no significant difference was identified. Moreover, in RA patients with sSS, mean ESR = 39 mm/h compared with mean CRP at 25 mg/l. 79% of all patients demonstrated dysproteinaemia. There were connections between higher ESR and dysproteinaemia. In the control group there was no statistically significant difference between CRP and ESR. CONCLUSIONS: Both DAS28-ESR and DAS28-CRP are useful outcome measures in RA. However, in patients with RA and sSS, DAS28 should be evaluated based on CRP.

Transforming growth factor Beta family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications.

The transforming growth factor beta (TGF-ß) family forms a group of three isoforms, TGF-ß1, TGF-ß2, and TGF-ß3, with their structure formed by interrelated dimeric polypeptide chains. Pleiotropic and redundant functions of the TGF-ß family concern control of numerous aspects and effects of cell functions, including proliferation, differentiation, and migration, in all tissues of the human body. Amongst many cytokines and growth factors, the TGF-ß family is considered a group playing one of numerous key roles in control of physiological phenomena concerning maintenance of metabolic homeostasis in the bone tissue. By breaking the continuity of bone tissue, a spread-over-time and complex bone healing process is initiated, considered a recapitulation of embryonic intracartilaginous ossification. This process is a cascade of local and systemic phenomena spread over time, involving whole cell lineages and various cytokines and growth factors. Numerous in vivo and in vitro studies in various models analysing cytokines and growth factors' involvement have shown that TGF-ß has a leading role in the fracture healing process. This paper sums up current knowledge on the basis of available literature concerning the role of the TGF-ß family in the fracture healing process.

Syndromes with chronic non-bacterial osteomyelitis in the spine.

Chronic non-bacterial osteomyelitis (CNO) has been known for over of 40 years. It is an underrecognized entity due to the low number of described cases and poor propagation awareness of the problem. Chronic non-bacterial osteomyelitis is usually confused with infectious spondylodiscitis or malignant lesions, both primary and metastatic. Failing to consider CNO as one of possible lesions of the spine among an array of differential diagnoses may lead to a prolonged ineffective treatment increasing treatment-related morbidity. In this paper the authors describe these two syndromes, with a possible autoimmune background - chronic recurrent multifocal osteomyelitis (CRMO) and SAPHO syndrome - that include CNO being among the manifestations. The authors present the spinal symptomatology of CNO for both syndromes published so far to help spine clinicians organize the information for better usage in everyday clinical practice.

The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis.

Osteoarthritis (OA) is the most common chronic disease of human joints. The basis of pathologic changes involves all the tissues forming the joint; already, at an early stage, it has the nature of inflammation with varying degrees of severity. An analysis of the complex relationships indicates that the processes taking place inside the joint are not merely a set that (seemingly) only includes catabolic effects. Apart from them, anti-inflammatory anabolic processes also occur continually. These phenomena are driven by various mediators, of which the key role is attributed to the interactions within the cytokine network. The most important group controlling the disease seems to be inflammatory cytokines, including IL-1 ß , TNF α , IL-6, IL-15, IL-17, and IL-18. The second group with antagonistic effect is formed by cytokines known as anti-inflammatory cytokines such as IL-4, IL-10, and IL-13. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of OA with respect to inter- and intracellular signaling pathways is still under investigation. This paper summarizes the current state of knowledge. The cytokine network in OA is put in the context of cells involved in this degenerative joint disease. The possibilities for further implementation of new therapeutic strategies in OA are also pointed.

Orthopedic procedures in patients with congenital coagulation disorders: single center experience.

BACKGROUND: Spontaneous intraarticular bleeds in congenital coagulation disorders result in early and extensive damage to the joints and periarticular structures. Total arthroplasty is the only effective method of treating these defects. Interim surgical procedures (arthroscopy, osteotomy, etc.) exist that can postpone arthroplasty, especially considering the fact that the condition affects young people. The aim of this paper is to discuss the range of trauma care and orthopedic procedures performed in patients with congenital coagulation disorders. Also presented are early results of joint arthroplasty in these patients. MATERIAL AND METHODS: A total of 168 trauma care and orthopedic procedures were performed in patients with congenital coagulation disorders at the Clinical Department of Orthopedics and Traumatology of the Central Clinical Hospital of the Ministry of Interior in Warsaw in the years 2010-2013. Among them were total arthroplasties (79 arthroplasties of the knee, 30 of the hip, 3 of the ankle and 1 of the elbow), arthroscopies, filling bone cysts with grafts and trauma procedures. The HHS, KSS, AOFAS and MEPS scales were used to evaluate the respective clinical results of hip, knee, ankle and elbow arthroplasty procedures. A VAS was used to evaluate pain intensity. In knee arthroplasty patients, quality of life parameters were evaluated with the WOMAC index. RESULTS: In patients post hip arthroplasty, HHS scores increased by 50.22 points and VAS scores increased by 6.34 points. An increase of 116.41 points in KSS scores and 6.67 points in VAS scores was recorded in patients after knee arthroplasty. Also, WOMAC scores improved by 53.8 points after surgery. Evaluation of early results of ankle arthroplasty in the AOFAS scale showed a mean improvement of 35.5 points and a 5-point improvement in VAS scores. MEPS scores, used for evaluation of elbow arthroplasty results, improved from 15 to 70 points, with an improvement from 6 to 2 points in VAS scores. CONCLUSIONS: 1. Orthopedic procedures in patients with congenital coagulation disorders require thorough preparation of the patient and close cooperation between the orthopedic and hematological teams. 2. Early clinical outcomes are promising. 3. Decreased pain intensity, increased joint range of motion and improved quality of life post-surgery are observed.