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Targeting strategies for bone diseases: signaling pathways and clinical studies.

Since the proposal of Paul Ehrlich's magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From the initial selective antibody, antitoxin to targeted drug delivery that emerged in the past decades, more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases. As a highly pyknotic mineralized tissue with lessened blood flow, bone is characterized by a complex remodeling and homeostatic regulation mechanism, which makes drug therapy for skeletal diseases more challenging than other tissues. Bone-targeted therapy has b

Ablation of retinal horizontal cells from adult mice leads to rod degeneration and remodeling in the outer retina.

In the brain, including the retina, interneurons show an enormous structural and functional diversity. Retinal horizontal cells represent a class of interneurons that form triad synapses with photoreceptors and ON bipolar cells. At this first retinal synapse, horizontal cells modulate signal transmission from photoreceptors to bipolar cells by feedback and feedforward inhibition. To test how the fully developed retina reacts to the specific loss of horizontal cells, these interneurons were specifically ablated from adult mice using the diphtheria toxin (DT)/DT-receptor system and the connexin5

Свойства антиракера ВИЧ-ингибатора Нелфинавира.

Традиционные методы лечения рака могут потерять свою эффективность после появления новых мутации или развития химиотерапии. Несвоевременная диагностика, высокая стоимость лечения и потребность в высокоэффективной инфраструктуре для лечения раковых заболеваний затрудняют доступ к надлежащему лечению в условиях с низким уровнем доходов и ограниченными ресурсами. Переориентация утвержденных лекарственных средств на лечение рака может привести к снижению стоимости и сокращению сроков разработки новых лекарственных средств и к ускорению появления новых и эффективных вариантов лечения для нуждающихс

Sox8: многогранный фактор транскрипции развития и болезней.

Sox8 — коэффициент транскрипции, который относится к семейству Sox в домене высокомобильной группы, содержащем белки, и тесно связан с Sox9 и Sox10. Во время дородового развития Sox8 выражается в нескольких эктодермовых, эндодермовых и мезодермовых тканях и причастно к процессам органогенеза и дифференциации. Выражение Sox8 встречается в ряде важных клеток, таких как клетки Sertoli в мужском гонаде, глиальные клетки, спутниковые клетки и хондроциты. Однако Sox8 не имеет существенного значения для надлежащей разработки любой из соответствующих систем, поскольку он работает излишне с Sox9 или So

Muscle and Bone Defects in Metastatic Disease.

PURPOSE OF REVIEW: The present review addresses most recently identified mechanisms implicated in metastasis-induced bone resorption and muscle-wasting syndrome, known as cachexia. RECENT FINDINGS: Metastatic disease in bone and soft tissues is often associated with skeletal muscle defects. Recent studies have identified a number of secreted molecules and extracellular vesicles that contribute to cancer cell growth and metastasis leading to bone destruction and muscle atrophy. In addition, alterations in muscle microenvironment including dysfunctions in hepatic and mitochondrial metabolism ha

Апиген как потенциальный модулятор нейроинфламмации в многоразовом склерозе: обзор.

Множественный склероз (MS) — хроническое воспалительное заболевание центральной нервной системы (CNS), характеризующееся нейроинфламмацией и обезвоживанием. Несмотря на то, что в течение последнего десятилетия расширились возможности лечения MS, нынешняя терапия направлена главным образом на периферийные иммунные системы и часто связана со значительными побочными эффектами. Кроме того, эта терапия до сих пор не предлагает решений для последующего нейродегенерации, сопровождающего развитие болезни. Результаты исследований, проведенных с использованием клеточных и животных моделей и исследований

Вирусы и "Мозг-отношение к беде".

Неврологические расстройства, некоторые из которых связаны с вирусными инфекциями, растут из-за старения и увеличения численности населения. Несмотря на крепкую защиту центральной нервной системы, некоторые вирусы эволюционировали, чтобы пробить их, что часто приводит к ужасным последствиям. В этом обзоре мы рассказываем о различных способах проникновения различных вирусов в ЦНС и о последствиях таких вторжений. Последствия могут проявляться в виде острых заболеваний, таких, как энцефалит, менингит, или приводить к долгосрочным последствиям, таким, как нервно - мышечная дисфункция, как это име

Совпадение в полном тексте источника
… Gap junctions consist of proteins from the connexin family [ 12 ], and play a role in cell proliferation and migration beyond intercellular communication [ 13 ]. The cytoskeleton linked to junction scaffolding proteins is also an indispensable component of intercellular connections. … Gap junctions are formed by two hemichannels in the plasma membranes of adjacent cells, which are composed of protein subunits called connexins. …

Osteocytes: New Kids on the Block for Cancer in Bone Therapy.

The tumor microenvironment plays a central role in the onset and progression of cancer in the bone. Cancer cells, either from tumors originating in the bone or from metastatic cancer cells from other body systems, are located in specialized niches where they interact with different cells of the bone marrow. These interactions transform the bone into an ideal niche for cancer cell migration, proliferation, and survival and cause an imbalance in bone homeostasis that severely affects the integrity of the skeleton. During the last decade, preclinical studies have identified new cellular mechanism

Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment.

Bone is the most common metastatic site in breast cancer. Upon arrival to the bone, disseminated tumor cells can undergo a period of dormancy but often eventually grow and hijack the bone microenvironment. The bone marrow microenvironment consists of multiple cell types including the bone cells, adipocytes, endothelial cells, and nerve cells that all have crucial functions in the maintenance of bone homeostasis. Tumor cells severely disturb the tightly controlled cellular and molecular interactions in the bone marrow fueling their own survival and growth. While the role of bone resorbing osteo

Resveratrol: Molecular Mechanisms, Health Benefits, and Potential Adverse Effects.

Resveratrol (RES), a naturally occurring polyphenolic compound, has garnered significant attention due to its diverse biological activities, which include anti-inflammatory, antioxidant, and antiaging properties. This review synthesizes current evidence concerning the molecular mechanisms, therapeutic efficacy, and safety profile of RES across a variety of pathologies, with an emphasis on the latest research conducted in recent years. Mechanistically, RES is known to modulate critical signaling pathways such as the activation of sirtuin 1. These actions collectively contribute to the attenuati

Pericytes as targets in hereditary hemorrhagic telangiectasia.

Defective paracrine Transforming Growth Factor-β (TGF-β) signaling between endothelial cells and the neighboring mural cells have been thought to lead to the development of vascular lesions that are characteristic of Hereditary Hemorrhagic Telangiectasia (HHT). This review highlights recent progress in our understanding of TGF-β signaling in mural cell recruitment and vessel stabilization and how perturbed TGF-β signaling might contribute to defective endothelial-mural cell interaction affecting vessel functionalities. Our recent findings have provided exciting insights into the role of thalid

Leukoencephalopathy During Daratumumab-Based Therapy: A Case Series of Two Patients with Multiple Myeloma.

Leukoencephalopathy in the setting of multiple myeloma (MM) is a rare demyelinating condition, with few reported cases in literature. Daratumumab is a CD38 targeted monoclonal antibody that has been widely used for the management of MM. In the absence of central nervous system (CNS) disease, many medication-induced leukoencephalopathy cases reported with MM, including daratumumab-induced, are associated with progressive multifocal leukoencephalopathy (PML) and John Cunningham (JC) virus. Currently, there are no reported cases of daratumumab-induced leukoencephalopathy among patients without CN

Epigenetic Regulation of Autophagy in Bone Metabolism.

The skeletal system is crucial for supporting bodily functions, protecting vital organs, facilitating hematopoiesis, and storing essential minerals. Skeletal homeostasis, which includes aspects such as bone density, structural integrity, and regenerative processes, is essential for normal skeletal function. Autophagy, an intricate intracellular mechanism for degrading and recycling cellular components, plays a multifaceted role in bone metabolism. It involves sequestering cellular waste, damaged proteins, and organelles within autophagosomes, which are then degraded and recycled. Autophagy's i

Совпадение в полном тексте источника
… Connexins and pannexins in the skeleton: gap junctions, hemichannels and more . Cell Mol Life Sci . 2015 ; 72 ( 15 ): 2853 – 2867 . 26091748 10.1007/s00018-015-1963-6 PMC4503509 139. Santos L , Elliott-Sale KJ , Sale C . Exercise and bone health across the lifespan . … Mechanotransduction via the coordinated actions of integrins, PI3K signaling and Connexin hemichannels . Bone Res . 2021 ; 9 ( 1 ): 8 . 33531460 10.1038/s41413-020-00126-w PMC7854719 163. Xu H , Xia M , Sun L , Wang H , Zhang WB . …

Silencing of SPARC represses heterotopic ossification via inhibition of the MAPK signaling pathway.

Heterotopic ossification (HO), the pathologic formation of extraskeletal bone, can be disabling and lethal. However, the underlying molecular mechanisms were largely unknown. The present study aimed to clarify the involvement of secreted protein acidic and rich in cysteine (SPARC) and the underlying mechanism in rat model of HO. The mechanistic investigation on roles of SPARC in HO was examined through gain- and loss-of-function approaches of SPARC, with alkaline-phosphatase (ALP) activity, mineralized nodules, and osteocalcin (OCN) content measured. To further confirm the regulatory role of S

The Circular Life of Human CD38: From Basic Science to Clinics and Back.

Monoclonal antibodies (mAbs) were initially considered as a possible "magic bullet" for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since canc

Взаимодействие между нейтрофилами и элементами барьера крови и мозга в контексте множественного склероза и ишемического разрушения.

Барьер мозга крови (BBB) представляет собой полупроницаемую мембрану в физиологических условиях, но в патологии, такой, как множественный склероз (MS) и ишемический инсульт (IS), его проницаемость возрастает. В этом обзоре основное внимание уделяется нейтрофильам и их взаимодействию с клеточными компонентами ББД: эндотелиальными клетками (ЭК), перицитами (ПХ) и астроцитами (АК). В настоящее время нейтрофилы получают больше внимания, главным образом благодаря передовым методам исследований, которые показывают сложность их населения. Кроме того, нейтрофилы способны засекать внеклеточные везикли

Совпадение в полном тексте источника
… VEGF induces BBB breakdown by downregulating the TJs proteins of ECs directly and also by activating MMP-9 to degrade connexins [ 12 , 127 ]. On the other hand, astrocytes may have a neuroprotective role and produce anti-inflammatory factors in ischemia [ 118 ]. …

Metastatic Spread in Prostate Cancer Patients Influencing Radiotherapy Response.

Radiotherapy and surgery are curative treatment options for localized prostate cancer (PCa) with a 5-year survival rate of nearly 100%. Once PCa cells spread into distant organs, such as bone, the overall survival rate of patients drops dramatically. The metastatic cascade and organotropism of PCa cells are regulated by different cellular subtypes, organ microenvironment, and their interactions. This cross-talk leads to pre-metastatic niche formation that releases chemo-attractive factors enforcing the formation of distant metastasis. Biological characteristics of PCa metastasis impacting on m

The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease.

The well-orchestrated turnover of proteins in cross-striated muscles is one of the fundamental processes required for muscle cell function and survival. Dysfunction of the intricate protein degradation machinery is often associated with development of cardiac and skeletal muscle myopathies. Most muscle proteins are degraded by the ubiquitin-proteasome system (UPS). The UPS involves a number of enzymes, including E3-ligases, which tightly control which protein substrates are marked for degradation by the proteasome. Recent data reveal that E3-ligases of the cullin family play more diverse and c

Translational Strategies to Target Metastatic Bone Disease.

Metastatic bone disease is a common and devastating complication to cancer, confounding treatments and recovery efforts and presenting a significant barrier to de-escalating the adverse outcomes associated with disease progression. Despite significant advances in the field, bone metastases remain presently incurable and contribute heavily to cancer-associated morbidity and mortality. Mechanisms associated with metastatic bone disease perpetuation and paralleled disruption of bone remodeling are highlighted to convey how they provide the foundation for therapeutic targets to stem disease escala

Ixazomib Improves Bone Remodeling and Counteracts sonic Hedgehog signaling Inhibition Mediated by Myeloma Cells.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of plasma cells (PC) in the bone marrow (BM), leading to bone loss and BM failure. Osteolytic bone disease is a common manifestation observed in MM patients and represents the most severe cause of morbidity, leading to progressive skeletal damage and disabilities. Pathogenetic mechanisms of MM bone disease are closely linked to PCs and osteoclast (OCs) hyperactivity, coupled with defective osteoblasts (OBs) function that is unable to counteract bone resorption. The aim of the present study was to investigate t