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A Review on the Molecular Mechanisms of Action of Natural Products in Preventing Bone Diseases.

The drugs used for treating bone diseases (BDs), at present, elicit hazardous side effects that include certain types of cancers and strokes, hence the ongoing quest for the discovery of alternatives with little or no side effects. Natural products (NPs), mainly of plant origin, have shown compelling promise in the treatments of BDs, with little or no side effects. However, the paucity in knowledge of the mechanisms behind their activities on bone remodeling has remained a hindrance to NPs' adoption. This review discusses the pathological development of some BDs, the NP-targeted components, an

Hijacking the helpers: platelet and neutrophil trafficking in AML and therapeutic exploitation.

Acute myeloid leukemia (AML) remains one of the most aggressive and treatment-resistant hematologic malignancies, driven by clonal expansion of immature myeloid blasts in the bone marrow and peripheral blood. Current therapies-chemotherapy and targeted agents-are limited by poor marrow penetration, systemic toxicity, and rapid development of resistant clones, leaving long-term survival rates low. Clinicians face the persistent challenge of delivering effective therapy while minimizing harm. Platelets and neutrophils-beyond their classical roles in hemostasis and innate immunity-actively suppor

Disruption of the microenvironmental ecosystem in subchondral bone marrow lesions: Roles in osteoarthritis pathophysiology, pain and progression.

This narrative review explores the role of subchondral bone in the pathophysiology of osteoarthritis (OA), emphasizing the biomechanical and biochemical contributions that it makes to disease progression. A fresh perspective is presented by the authors in the form of a novel hypothesis that implicates mechano-inflammatory disruption of the bone marrow (BM) microenvironmental ecosystem (BM niche), unresolved inflammation, and fibrosis as key drivers of OA pathogenesis and pain. BMLs, detectable via magnetic resonance imaging (MRI), serve as dynamic imaging biomarkers that correlate with pain se

Autophagy in tumor immune escape and immunotherapy.

The immunotherapy targeting tumor immune escape mechanisms has become a critical strategy in anticancer treatment; however, the challenge of immune resistance remains significant. Autophagy, a cellular response to various stressors, involves the degradation of damaged proteins and organelles via lysosomal pathways, maintaining cellular homeostasis. This process not only supports tumor cell survival but also profoundly impacts the efficacy of cancer immunotherapies. The modulation of autophagy in tumor cells or immune cells exerts dual effects on tumor immune escape and immunotherapy. However,

Cancer-Associated Thrombosis in Patients Treated with Immune Checkpoint Inhibitors.

The incidence of cancer-associated thrombosis has increased in recent years. While the association between venous thromboembolism (VTE) and chemotherapy is well established, there is no clear link between immune checkpoint inhibitors (ICIs) and VTE risk. Many risk assessment models (RAMs) have been developed to identify high-risk patients who need prophylaxis. However, these models are validated in patients undergoing chemotherapy, while they are scarce in those receiving immunotherapy. Moreover, the mechanisms linking ICIs to thrombosis are still a matter of debate. They include the upregulat

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… Neutrophil extracellular traps kill bacteria Science 2004 303 1532 1535 10.1126/science.1092385 15001782 61. Shim Y.J. Rayman P. Pavicic P. Swaidani S. Khorana A.A. Diaz-Montero M. McCrae K.R. … Neutrophil extracellular traps in immunity and disease Nat. Rev. Immunol. 2018 18 134 147 10.1038/nri.2017.105 28990587 78. Cedervall J. Zhang Y. Olsson A.K. …

Risk assessment and prevention of cancer-associated venous thromboembolism in ambulatory patients with solid malignancies.

Venous thromboembolism remains a major cause of morbidity and mortality among ambulatory cancer patients, necessitating effective risk assessment and prevention strategies. Despite the availability of risk assessment models and guidelines recommending primary thromboprophylaxis with low-molecular-weight heparins or direct oral anticoagulants, the application of these strategies is inconsistent. This review provides an overview of the current state-of-the-art venous thromboembolism risk assessment and thromboprophylaxis in ambulatory patients with cancer, focusing on existing risk assessment mo

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… Impact of neutrophil extracellular traps on thrombosis formation: new findings and future perspective. Front Cell Infect Microbiol. 2022;12 doi: 10.3389/fcimb.2022.910908. 48. Seo J.D., Gu J.Y., Jung H.S., Kim Y.J., Kim H.K. … Contact system activation and neutrophil extracellular trap markers: risk factors for portal vein thrombosis in patients with hepatocellular carcinoma. Clin Appl Thromb Hemost. 2019;25 doi: 10.1177/1076029618825310. 49. …

Histone deacetylase in inflammatory bowel disease: novel insights.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is characterized by chronic nonspecific intestinal inflammation. Despite considerable efforts, IBD remains a heavy burden on society and human health, with increasing morbidity. Posttranslational modification, especially histone acetylation, is a key process in controlling DNA transcriptional activity. Histone deacetylases (HDACs) play a vital role in the mechanism of IBD pathogenesis through histone and nonhistone protein deacetylation. Herein, we present a summary of different categories of HDACs as well as H

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… Butyrate has been shown to significantly alleviate mouse colitis via the inhibition of neutrophil-associated immune responses and neutrophil extracellular traps formation. 118 A butyrate-releasing derivative, N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), has been reported to inhibit HDAC9, restore … BMDM, bone marrow-derived macrophages; HDAC, histone deacetylase; LP, lamina propria; LPS, lipopolysaccharide; NET, neutrophil extracellular trap; PBMC, peripheral blood mononuclear cell; SOCS1, suppressor of cytokine signaling 1; Tregs, regulatory T cells; VDR, vitamin D receptor. …

IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit β (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete th

A novel application perspective of the clinical-used drug verapamil on osteoporosis via targeting Txnip.

BACKGROUND: RANKL and SCLEROSTIN antibodies have provided a strong effective choice for treating osteoporosis in the past years, which suggested novel molecular target identification and therapeutic strategies development are important for the treatment of osteoporosis. The therapeutic effect of verapamil, a drug previously used for cardiovascular diseases, on diabetes was due to the inhibition of TXNIP expression, which has also been reported as a target in mice osteoporosis. Whether verapamil-inhibited TXNIP expression is related to osteoporosis and how it works on the molecular level is wor

Cellular and Molecular Mechanisms Associating Obesity to Bone Loss.

Obesity is an alarming disease that favors the upset of other illnesses and enhances mortality. It is spreading fast worldwide may affect more than 1 billion people by 2030. The imbalance between excessive food ingestion and less energy expenditure leads to pathological adipose tissue expansion, characterized by increased production of proinflammatory mediators with harmful interferences in the whole organism. Bone tissue is one of those target tissues in obesity. Bone is a mineralized connective tissue that is constantly renewed to maintain its mechanical properties. Osteoblasts are responsib

Macrophage miR-149-5p induction is a key driver and therapeutic target for BRONJ.

Bisphosphonate-related (BP-related) osteonecrosis of the jaw (BRONJ) is one of the severe side effects of administration of BPs, such as zoledronic acid (ZA), which can disrupt the patient's quality of life. Although the direct target of skeletal vasculature and bone resorption activity by BPs has been phenomenally observed, the underlying mechanism in BRONJ remains largely elusive. Thus, it is urgently necessary to discover effective therapeutic targets based on the multifaceted underlying mechanisms in the development of BRONJ. Here, we determined the inhibitory role of ZA-treated macrophage

The Role of TAM Receptors in Bone.

The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis

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… As soluble TAM receptors serve as extracellular traps for TAM ligands, these results suggest that PROS1 or GAS6 might dampen osteoclastogenesis. …

An Italian cartography of VEXAS-related thrombosis.

Thrombotic events (TEs) occur in up to 40% of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic (VEXAS) syndrome, but data on its clinical-genomics features and anticoagulation strategies are limited. To gain more insight into this, we conducted a two-step study evaluating the prevalence and outcome of TE in VEXAS. First, among 1086 patients followed for TEs, 198 were men aged >40 years with unprovoked thrombosis and no known thrombophilia; 21 also had at least one VEXAS-compatible feature and underwent UBA1 exon 3 testing. No UBA1 mutation was detected in these 21 pat

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… NETworking with cancer: the bidirectional interplay between cancer and neutrophil extracellular traps. Cancer Cell. 2023;41(3):505‐526. 10.1016/j.ccell.2023.02.001 15. Mekinian AM, Georgin‐Lavaille S, Ferrada MA, et al. … Platelets and neutrophils cooperate to induce increased neutrophil extracellular trap formation in JAK2 V617F myeloproliferative neoplasms. J Thromb Haemost. 2024;22(1):172‐187. 10.1016/j.jtha.2023.08.028 32. Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. …

Регулярная молекула-а регулирует ответные реакции, связанные с нейтрофильом TH17 в CNS автоиммунитет.

МЯСО И АЙМ: Отталкивающая молекула наведения-А (RGMA) хорошо известна своей ролью в нейро-воспалении и ремонте CNS с помощью Т-образных клеток. Врожденные иммунные взаимодействия, особенно между нейтрофилами и клетками TH17, становятся критическими движущими силами нейроинфламматической патологии в множестве склерозов (MS). Вопрос о том, регулирует ли РГМ эти связанные с нейтрофильом ответы TH17, остается в значительной степени неизвестным. Уточнение этого механизма может выявить новые терапевтические цели для НР. МЕТОДЫ: Уровни сера РГМ, БМП4, нейтрофильная эластаза (NE), IL-17A, и подстрекат

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… Concurrently, neutrophils, once considered secondary responders, are now recognized as active contributors to neuroinflammation, instigating tissue injury through the release of soluble mediators and neutrophil extracellular traps (NETs) ( 14 , 15 ). … Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis . Science . ( 2015 ) 349 : 316–20 . doi: 10.1126/science.aaa8064 26185250 PMC4854322 26 Liu J Tao P Su B Zheng L Lin Y Zou X . …

The Bone Extracellular Matrix as an Ideal Milieu for Cancer Cell Metastases.

Bone is a preferential site for cancer metastases, including multiple myeloma, prostate, and breast cancers.The composition of bone, especially the extracellular matrix (ECM), make it an attractive site for cancer cell colonization and survival. The bone ECM is composed of living cells embedded within a matrix composed of both organic and inorganic components. Among the organic components, type I collagen provides the tensile strength of bone. Inorganic components, including hydroxyapatite crystals, are an integral component of bone and provide bone with its rigidity. Under normal circumstance

Exploring the Vasculitis-Tumors Link: Epidemiological Patterns, Mechanistic Insights, and Clinical Implications.

This review systematically examines the association between vasculitis and malignancies by summarizing the risk of tumor-associated vasculitis, their clinical characteristics, and proposed pathogenic mechanisms across different vasculitic subtypes. Relevant case reports and mechanistic studies are integrated to provide a comprehensive overview of this entity. The findings offer practical value for rheumatologists in distinguishing primary vasculitis from malignancy-associated forms and optimizing patient surveillance, and for oncologists in improving recognition of tumor-associated vasculitis

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… Neutrophil extracellular traps (NETs), which consist of myeloperoxidase (MPO)–elastase complexes, further exacerbate chromatin damage within inflamed tissues [ 21 ]. … D., Hakkim A., and Zychlinsky A., “Neutrophil Elastase and Myeloperoxidase Regulate the Formation of Neutrophil Extracellular Traps,” Journal of Cell Biology 191, no. 3 (2010): 677–691. 22. …

Secondary Immunodeficiency in Hematological Malignancies: Focus on Multiple Myeloma and Chronic Lymphocytic Leukemia.

Secondary immunodeficiency is reported in most patients with hematological malignancies such as chronic lymphocytic leukemia and multiple myeloma. The aim of our review was to evaluate the existing literature data on patients with hematological malignancies, with regard to the effect of immunodeficiency on the outcome, the clinical and therapeutic approach, and on the onset of noninfectious complications, including thrombosis, pleural effusion, and orofacial complications. Immunodeficiency in these patients has an intense impact on their risk of infection, in turn increasing morbidity and mort

Dissecting Bone Marrow Fibrosis in Philadelphia-Negative Myeloproliferative Neoplasms: Multiple Roads Lead to Rome.

Philadelphia-negative myeloproliferative neoplasms (MPN), a spectrum of blood malignancies characterized by uncontrolled myeloid proliferation, persist as a key challenge in onco-hematology due to their intricate molecular background, heterogeneous clinical phenotypes, and variable prognoses. Although generally accepted as indolent disorders, a considerable fraction of MPN patients exhibit progressive, and sometimes accelerated, bone marrow fibrosis, reflecting a critical shift toward a more debilitating condition marked by an increased symptom burden. As marrow scarring advances, hematopoieti

Novel therapies emerging in oncology to target the TGF-β pathway.

The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based

A review on how to do hematology consults during COVID-19 pandemic.

The ongoing COVID-19 pandemic is the most trending and talked topic across the World. From its point of origin in Wuhan, China to clinical laboratory at NIH, a mere six-month-old SARS-CoV-2 virus is keeping the clinicians, and scientists busy at various fronts. However, COVID-19 is an emerging and evolving disease and each day brings in more data, new figures, and findings from the field of clinical practice. The role of hematologists has been increasingly recognized during the current pandemic because of several reasons. Most important of them are the characteristic hematological findings of

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… Neutrophil extracellular traps (NETs) Neutrophils are considered as the first line of defense of anyone's immune system. Neutrophils act via engulfment of microbes, secretion of anti-microbials, and formation of Neutrophil Extracellular Traps (NETs) [ 62 ]. … Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–1535. doi: 10.1126/science.1092385. 63. Brenner S.R. …