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Распознавание ксантиновой реберосколочной структуры и металлическое ионопосредованное распознавание лиганда.

Рибосколки сохраняют функциональные области в MRNA, которые в основном существуют в бактериях. Они регулируют генное выражение в ответ на различные концентрации метаболитов или металлических ионов. Недавно был выявлен мотив РНК NMT1 для селективной привязки ккантиновой и мочевой кислот, соответственно, к метаболическому пути деградации пурины. Вот, мы сообщаем о кристаллической структуре этой РНК, связанной с ксантиной. В целом рибосуха имеет стержень, постоянно сложенный в сложенном виде three стебли и two внутренние перекрестки. Связующий карман определяется высокоохранной соединенной послед

Nanogel-Based Precision Bone Regeneration: Rational Design, Biological Barrier Penetration, and Osteoporotic Microenvironment Remodeling.

The pathogenesis of osteoporosis is primarily associated with impaired communication between osteoblasts and osteoclasts, leading to disrupted bone homeostasis. Conventional biomaterials mainly rely on macroscopic structural support and are limited in their ability to precisely regulate the complex bone microenvironment and overcome biological barriers. As representative soft matter nanoplatforms, nanogels possess unique viscoelastic mechanical properties and adaptive biointerfacial properties, offering new opportunities to overcome physical barriers within bone tissues. Moving beyond previous

Cancer Immunotherapy in Combination with Radiotherapy and/or Chemotherapy: Mechanisms and Clinical Therapy.

Since the United States Food and Drug Administration approved the first immune checkpoint inhibitor ipilimumab for metastatic melanoma in 2011, ICIs have been approved for a range of cancers and significantly improving treatment outcomes. However, the objective response rate of ICI monotherapy remains modest (10-40%), with clinical benefit observed in only 15-20% of patients. The limited efficacy of ICIs in many patients is often attributed to poorly immunogenic ("cold") tumors. Radiotherapy and chemotherapy exhibit immunomodulatory properties that can enhance tumor immunogenicity. These effec

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… cGAS–STING After RT, cells can experience DNA double‐strand breaks (DSBs), which are detected by the cyclic GMP‐AMP synthase (cGAS) protein sensor [ 122 , 145 ]. … This recognition triggers the synthesis of cyclic GMP‐AMP (cGAMP), which serves as a secondary messenger. cGAMP activates and binds to the stimulator of IFN genes (STING), prompting its translocation from the ER to the Golgi apparatus [ 146 , 147 ]. …

Диметилфумарат уменьшает травму от печени ишемии и реперуляции путем подавления сигнала CGAS-STING.

Повреждение печени во время периоперационной фазы операции на печени часто происходит в результате печени. Неправильная активация сигнала СТИНГ может вызвать чрезмерную воспламенение реакции на усугубление печени. Диметилфумарат (DMF) — разрешенный УЛХ иммунодулятор, используемый для лечения множественного склероза и псориаза в силу его заметных свойств против воспаления. Однако механизм и целевые показатели ДМФ в области иммуномодуляции остаются неясными. Здесь мы обнаружили, что DMF подавляет активацию CGAS-STING, индуцируемую HSV-1, ДНК яичек и митохондриальная ДНК в различных клетках. DMF

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… In this study, our findings indicate DMF strongly inhibits the activation of innate immunity in cGAS‐STING pathway by cGAS ligands (mitochondrial DNA [mtDNA], HTDNA, and HSV‐1) or STING agonists (cyclic GMP‐AMP [cGAMP] and diABZI). …

Revisiting potential value of antitumor drugs in the treatment of COVID-19.

Since an outbreak started in China in 2019, coronavirus disease 2019 (COVID-19) has rapidly become a worldwide epidemic with high contagiousness and caused mass mortalities of infected cases around the world. Currently, available treatments for COVID-19, including supportive care, respiratory support and antiviral therapy, have shown limited efficacy. Thus, more effective therapeutic modalities are highly warranted. Drug repurposing, as an efficient strategy to explore a potential broader scope of the application of approved drugs beyond their original indications, accelerates the process of d

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… In mammalian cells, cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, and its downstream signaling effector stimulator of interferon genes (STING), form a major DNA sensing mechanism. … Abbreviations Angiotensin-converting enzyme 2 Protein kinase B Bruton's tyrosine kinase Chimeric antigen receptor T cell Cyclic GMP-AMP synthase Casein kinase II Coronavirus disease 2019 Direct-acting antiviral agents Dimeric amidobenzimidazole Half maximal effective concentration Eukaryotic …

Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects.

The prognosis of patients with systemic lupus erythematosus has greatly improved since treatment regimens combining corticosteroids and immunosuppressive medications have been widely adopted in therapeutic strategies given to these patients. Immune suppression is evidently efficient but also leads to higher susceptibility to infectious and malignant diseases. Toxic effects and sometimes unexpectedly dramatic complications of current therapies have been progressively reported. Identifying novel molecular targets therefore remains an important issue in the treatment of lupus. The aim of this rev

New and Emerging Therapeutic Drugs for the Treatment of Pulmonary Arterial Hypertension: A Systematic Review.

Pulmonary arterial hypertension (PAH) is a serious, progressive, and potentially fatal lung disease characterized by a gradual increase in mean pulmonary arterial pressure to over 20 mmHg at rest. The pathogenesis of PAH is multifactorial. It involves dynamic obstruction of the pulmonary vasculature through vasoconstriction, structural obstruction due to adverse vascular remodeling, and pathological obstruction caused by vascular fibrosis and stiffening, which reduces compliance. PAH often presents with vague initial symptoms and is frequently diagnosed at an advanced stage. The increased pulm

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… Consequently, this leads to an elevation in cyclic GMP (cGMP) levels [ 39 ]. It has gained approval for its application in the treatment of PAH [ 3 ]. …

Effects of exosomes from different origins on osteoclasts.

Abnormal osteoclast function is closely related to the development of osteolytic diseases such as osteoporosis and tumor bone metastasis, which seriously affects patients' quality of life. The cellular microenvironment is complex and variable, and exosomes, as an important pathway mediating intercellular communication, can be secreted by a variety of cells in the human body, which carry "cargo" that can affect the biological function of recipient cells. Osteoclasts receive a variety of cellular exosomes to regulate and influence the body's bone homeostasis. In this narrative review, we summari

Targeting cytokine and chemokine signaling pathways for cancer therapy.

Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and o

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… Notably, many cancer treatment strategies, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, highly rely on the activation of IFN-I signaling pathways, especially the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. 3 IFN-α and engineered IFN-α administration … GMP-AMP (cGAMP) and a change in the conformation of STING (Fig. 3 ). 64 , 65 STING dimers are then translocated from the ER to perinuclear microsomes via the Golgi apparatus. …

Targeting the P-selectin/PSGL-1 pathway: discovery of disease-modifying therapeutics for disorders of thromboinflammation.

P-selectin is a membrane glycoprotein and a member of the selectin family of cell adhesion molecules. It is prestored in α-granules of platelets and Weibel-Palade bodies of endothelial cells and is rapidly expressed on their surfaces upon activation during the course of an inflammatory response. Although a critical component of the innate immune system, the interaction of P-selectin with its cognate ligand, P-selectin glycoprotein ligand 1 (PSGL-1) may mediate maladaptive events central to the pathophysiology of venous thromboembolism, cardiovascular disease, stroke, metabolic syndrome, and si

Emerging disease-modifying therapies for sickle cell disease.

Sickle cell disease afflicts millions of people worldwide and approximately 100,000 Americans. Complications are myriad and arise as a result of complex pathological pathways 'downstream' to a point mutation in DNA, and include red blood cell membrane damage, inflammation, chronic hemolytic anemia with episodic vaso-occlusion, ischemia and pain, and ultimately risk of cumulative organ damage with reduced lifespan of affected individuals. The National Heart, Lung, and Blood Institute's 2014 evidence-based guideline for sickle cell disease management states that additional research is needed bef

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… Soluble guanylate cyclase catalyzes the production of cyclic GMP, which promotes vascular health. 86 One agent, Riociguat ® , has been shown to improve function (increased 6-minute walk distance) and decrease vascular resistance in patients with pulmonary hypertension without SCD ( NCT00855465 ). 87 …

The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.

The cGAS-STING pathway acts as a critical molecular hub connecting genomic instability with cellular senescence. Functioning as a key regulator of the innate immune system, this pathway detects aberrant cytoplasmic DNA to activate downstream inflammatory responses, thereby playing a pivotal role in aging-related diseases. This review systematically explores the core mechanisms by which the cGAS-STING pathway regulates cellular senescence, emphasizing its role in triggering senescence through the recognition of DNA damage signals (e.g., oxidative stress, telomere dysfunction) and promoting para

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… Standing at the nexus of these phenomena is the cGAS-STING (cyclic GMP-AMP synthase–stimulator of interferon genes) innate immune pathway, which functions as a principal molecular conduit integrating genomic instability with chronic inflammation and cellular senescence [ 13 ]. … Acting as a cytosolic DNA sensor, cGAS responds to aberrant double-stranded DNA (dsDNA) by catalyzing the synthesis of the second messenger cyclic GMP-AMP (cGAMP) [ 14 ]. …

Воздействие витамина D на герпесвирусные инфекции.

Помимо своей классической роли в регулировании метаболизма кальция и фосфата, витамин D также оказывает значительное влияние на модуляцию иммунитета. Витамин D регулирует иммунную реакцию, переходя от воспламенительного состояния к более толерогенному one путем увеличения выброса антивоспалительных цитокинов при одновременном ослаблении регулирования проинфламаторных цитокинов. Таким образом, низкий уровень витамина D связан с повышенным риском возникновения аутоиммунных заболеваний, таких, как множественный склероз и тип 1 диабет. Кроме того, этот прохормон также способствует высвобождению хо

Poly(ADP-Ribose) Polymerase Inhibitors in Pancreatic Cancer: A New Treatment Paradigms and Future Implications.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy. Most of the patients of PDAC present at later stages of disease and have a five-year survival rate of less than 10%. About 5-10% PDAC cases are hereditary in nature and have DNA damage repair (DDR) mutations such as BRCA 1 and 2. Besides having implications on screening and prevention strategies, these mutations can confer sensitivity to platinum-based therapies and determine eligibility for poly(ADP-ribose) polymerase inhibitors (PARPi). In the presence of DDR mutations and PARPi, the cells are unable to utilize the error-fr

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… Exposure of double stranded DNA in cytoplasm activates cyclic GMP-AMP synthase (cGAS) and catalyzes production of cyclic-dinucleotide (CDN) ( Figure 2 B, 2–4), which activates STING with subsequent activation of either the NF-κB or the TBK1- IRF3-Type I IFN pathways ( Figure 2 B, 5–8) [ 89 ]. …

Breaking Therapy Resistance: An Update on Oncolytic Newcastle Disease Virus for Improvements of Cancer Therapy.

Resistance to therapy is a major obstacle to cancer treatment. It may exist from the beginning, or it may develop during therapy. The review focusses on oncolytic Newcastle disease virus (NDV) as a biological agent with potential to break therapy resistance. This avian virus combines, upon inoculation into non-permissive hosts such as human, 12 described anti-neoplastic effects with 11 described immune stimulatory properties. Fifty years of clinical application of NDV give witness to the high safety profile of this biological agent. In 2015, an important milestone was achieved, namely the succ

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… Cytosolic nonself DNA recognition via the cyclic GMP-AMP synthase (cGAS) pathway also leads to IFN-I induction [ 32 ]. Upon sensing DNA viruses, RNA polymerase III is reverse transcribed to produce short RNAs, which are recognized by RIG-I. …

Применение мезенхимальных ячеек и их эксзоом в нейродегенеративных заболеваниях и лизосомных заболеваниях.

Мезенхимальные стромальные клетки (МСЦ) стали перспективной терапевтической платформой для расстройств центральной нервной системы, включая нейродегенеративные заболевания и лизосомные расстройства хранения (ЛСД). В настоящем обзоре рассматриваются механизмы КБМ, связанные с активностью паракрина, иммуномодуляцией, воздействием антиоксидантов, регулированием с помощью ТФЭБ, а также с ферментатической перекрестной корректировкой в ЛСД, хотя и критически оцениваются проблемы перевода. Мы проводим сравнительный анализ источников КБМ, административных маршрутов, дозирующих режимов и характеристик

Мак-1 регулирует иммуноусилительное подавление конкретной стадии болезни через нитриковый путь в аутоиммунном заболевании.

Интегрин Мак-1 играет важнейшую роль в развитии множественного склероза (MS); однако лежащий в его основе механизм не в полной мере изучен. Здесь мы разработали мышь с миелоидной мышью Мак-1-дефицит. Используя экспериментальную аутоиммунную энцефаломиэлит (EAE) модель мыши MS, мы сообщаем, что Мак-1 на миелиоидных клетках является ключом к развитию болезней. Наши данные показывают, что миелиоидный Мак-1 значительно повышает интенсивность EAE и затрудняет регрессию заболеваний. Потеря Mac-1 увеличивает количество клеток Gr-1+ в периферийных тканях и CNS и предпочтительно ускоряет переход моноци

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… Ingenuity pathway analysis (IPA) of the DEGs revealed the activation of major IFN-associated pathways in Mac-1–deficient cells, including the Cyclic GMP-AMP Synthase (cGAS)–Stimulator of Interferon Genes (STING) pathway, activation of IFN regulatory factors, cytokine production, chemokine signaling, …

Chloroquine Restores eNOS Signaling in Shunt Endothelial Cells via Inhibiting eNOS Uncoupling.

Pulmonary arterial hypertension (PAH) is characterized by increased lung vascular stiffness and impaired vessel relaxation, primarily due to reduced nitric oxide (NO) production in endothelial cells. Recent studies indicate that chloroquine, an autophagy inhibitor, may help lower pulmonary arterial pressure and enhance lung vascular function. This study investigates the mechanisms underlying the chloroquine-mediated restoration of NO bioavailability in endothelial cells derived from aortopulmonary shunt lambs, a relevant model for congenital heart defect (CHD)-associated PAH. We found that NO

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… Once produced, NO diffuses into surrounding smooth muscle cells, activating soluble guanylate cyclase and raising cyclic GMP (cGMP) levels, leading to vasodilation [ 18 ]. …

Декодирование автономного иммунитета: распознает нейромиэлит оптику и ее связь с другими аутоиммунными неврологическими расстройствами.

Оптика нейромиелита (NMO) является редким, но изнурительным аутоиммунным заболеванием, характеризующимся сильным приступом оптического невравита и поперечного миелита, что часто приводит к значительным неврологическим расстройствам. Автоантиорганы, предназначенные для аквапорина-4 (AQP4) и миэлина олигодендроцита гликпротеина (MOG), играют важнейшую роль в патогенезе болезней, а терапевтические стратегии, включающие иммунодепрессивную терапию и новые биологи, используются для борьбы с заболеваниями и предотвращения рецидивов. Хотя исследования указывают на возможное дублирование между НМО и др

Abscopal Effects in Metastatic Cancer: Is a Predictive Approach Possible to Improve Individual Outcomes?

Patients with metastatic cancers often require radiotherapy (RT) as a palliative therapy for cancer pain. RT can, however, also induce systemic antitumor effects outside of the irradiated field (abscopal effects) in various cancer entities. The occurrence of the abscopal effect is associated with a specific immunological activation in response to RT-induced cell death, which is mainly seen under concomitant immune checkpoint blockade. Even if the number of reported apscopal effects has increased since the introduction of immune checkpoint inhibition, its occurrence is still considered rare and

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… In the cytoplasm of irradiated cells, cyclic GMP-AMP synthase (cGAS) binds to translocated double-stranded DNA fragments (dsDNA) induced by RT and activates a signaling cascade via the second messenger 2′3′-cGAMP (cGAMP) and stimulator of interferon genes (STING) to produce type I interferons (IFNs) …