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The potential therapeutic role of extracellular vesicles in critical-size bone defects: Spring of cell-free regenerative medicine is coming.

In recent years, the incidence of critical-size bone defects has significantly increased. Critical-size bone defects seriously affect patients' motor functions and quality of life and increase the need for additional clinical treatments. Bone tissue engineering (BTE) has made great progress in repairing critical-size bone defects. As one of the main components of bone tissue engineering, stem cell-based therapy is considered a potential effective strategy to regenerate bone tissues. However, there are some disadvantages including phenotypic changes, immune rejection, potential tumorigenicity,

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… | Mixing EVs with drugs or reagents and then process by sonication treatment | More exogenous substances could be loaded with higher loading efficiency | The integrity of the EVs membrane is destroyed with uncontrollable loading capacity of target drugs | Kim et al. (2016) Freezing/thawing | Rapid freezing … Currently, engineered EVs can be prepared by incubation, electroporation, sonication, mechanical extrusion, recurrent freezing and thawing, and direct EV surface modification by applying covalent or non-covalent interactions ( Liao et al., 2019 ). …

Fasting boosts breast cancer therapy efficacy via glucocorticoid activation.

The majority of breast cancers are driven by oestrogen receptor-α (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients1. However, resistance is common and tumours often progress after years of endocrine suppression2. Periodic fasting enhances the efficacy of standard endocrine therapy and delays acquired drug resistance, although the underlying mechanisms remain unclear3. Here we show that fasting induces extensive epigenetic reprogramming in ERα-positive breast cancer xenografts when combined with endocrine therapy, with large-scale activation of glucoc

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… Cells were then lysed and sonicated accordingly to the protocol previously described 45 , with the difference of have performed 15 cycles of 30 s on, 30 s off in the sonication step (BioRuptor Pico, Diagenode). …

Targeted therapy in pediatric central nervous system tumors: a review from the National Pediatric Cancer Foundation.

Central nervous system tumors represent the leading cause of cancer-related mortality in children. Conventional therapies of surgery, radiation, and cytotoxic chemotherapy have insufficient efficacy for some pediatric CNS tumors and are associated with significant morbidity, prompting an ongoing need for novel treatment approaches. Identification of molecular alterations driving tumorigenesis has led to a rising interest in developing targeted therapies for these tumors. The present narrative review focuses on recent progress in targeted therapies for pediatric CNS tumors. We outline the key i

Novel agents for advanced pancreatic cancer.

Pancreatic cancer is relatively insensitive to conventional chemotherapy. Therefore, novel agents targeting dysregulated pathways (MAPK/ERK, EGFR, TGF-β, HEDGEHOG, NOTCH, IGF, PARP, PI3K/AKT, RAS, and Src) are being explored in clinical trials as monotherapy or in combination with cytotoxic chemotherapy. This review summarizes the most recent advances with the targeted therapies in the treatment of patients with advanced pancreatic cancer.

Идентификация NLRP3PYD Homo-Oligomerization Inhibitors с антивоспалительной активностью.

Инфламасомы представляют собой многопротеиновые комплексы, которые представляют собой важнейшие элементы подстрекательской реакции. Регулирование дискриминированного комплекса NLRP3 инфламасома связано с патогенезом таких заболеваний, как множественный склероз, тип 2 сахарный диабет, болезнь Альцгеймера и рак. Несмотря на наличие молекулярных ингибиторов, специфичных для различных компонентов воспламенительных комплексов, в настоящее время ни о каких ингибиторах не сообщается конкретно для NLRP3PYD гомо-олигомеризации. В настоящем исследовании мы описываем идентификацию QM380 и QM381 в качеств

Targeted phytotherapy: essential oils, multi-target cancer action & nanodelivery.

Biochemical components of essential oils (EOs) are an innovative but largely underexplored type of precision phytotherapy (PT) in oncology owing to their anticancer activity against many types of tumors. This article discusses the important multitargeted molecular mechanisms of EOs (apoptosis, cell cycle arrest, angiogenesis, metastasis, tumor microenvironment) and their role as antitumor agents. In particular, an effort has been made to emphasize on the most notable volatile EOs such as thymol, eugenol, limonene, β-caryophyllene, and their interaction with oncogenic signaling pathways (NF-κB,

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… . | ( 111 ) Copaiba oil ( Copaifera langsdorffii ) | Hot emulsion with sonication (HES) | oNLC, oNLC-Plu1%, oNLC-Chol0.05%, oNLC-Chi0.1%, oNLC-PEG1% | Nanostructured lipid carriers (NLCs) | β-caryophyllene (67.8%), α-humulene (9.6%), α-copaene (4.7%) | Particle size: 151–232 nm; PDI: 0.11–0.17; ζ-potential … 0.019%; No toxicity to PNT2; Inhibited cell migration; Changed cell morphology; In vivo : reduced tumor size (TH-NLC 89.65% reduction) and angiogenesis | ( 119 ) Geraniol (from essential oils of plants like Monarda fistulosa , palmarosa, Thymus daenensis , rose, citronella) | Homogenization with ultra-sonication …

PEX11B Palmitoilation пары пероксисомальная дисфункция с клетками Шванна не работают в диабетической нейропатии.

Диабетическая нейропатия (ДН) является распространенным и болезненным осложнением диабета; однако механизмы, лежащие в основе ее патогенеза, остаются неясными, а эффективные клинические методы лечения отсутствуют. Цель этого исследования заключается в изучении роли пероксисома в клетках Шванна в DN. МЕТОДЫ: Изобилие пероксисома в акустических нервах мышей или клеток Шванна анализировалось с помощью лазерной суперразрешительной съемки и западного пятна. Пробоотборник RPF-GPF-SKL (Ser-Lys-Leu) использовался для оценки уровней пексафагии (пероксисомы-автофагика). Для оценки пальмитоилирования PEX

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… The cell lysates were then subjected to sonication at 4 °C in the NEM-fortified lysis buffer, and the resultant supernatants were incubated with anti-Flag beads from Smart-Lifesciences (SA042005) at the same temperature for a duration of 2 h. …

Дифференцированное выражение и модуляция ЭБИ2 и 7α,25-OHC синтезирующих (CH25H, CYP7B1) и унижающих достоинство (HSD3B7) ферментов в мышах и человеческих сосудистых клетках.

Внутренние лиганды рецептора EBI2, оксистерина 7α,25OHC, имеющие решающее значение для иммунной реакции, тщательно регулируются ферментами CH25H, CYP7B1 и HSD3B7. Линфоидные стромальные клетки и фолликулярные дендритические клетки внутри Т-клеток поддерживают градиент 7α,25OHC, при этом стромальные клетки увеличиваются, а дендритные клетки уменьшают их концентрацию. Этот градиент имеет ключевое значение для надлежащего размещения клеток В в лимфоидной ткани. В животной модели множественного склероза экспериментальный аутоиммунный энцефаломиэлит, уровни 7α,25OHC быстро увеличиваются в центральн

Новые клеточные модели для изучения взаимодействия Мьелин и Микроглиа.

Множественный склероз (MS) характеризуется обезвоживанием и нейроинфламмацией, при этом окислительный стресс играет ключевую роль в патологии поражения. Цель этого исследования заключалась в изучении дифференциальной реакции клеток на миелиновый мусор в различных окислительных состояниях. Окисление Myelin было вызвано с помощью системы Cuperoxid, что подтверждается повышенными уровнями TBARS и автофлюоресценцией. Из-за воздействия миелина на жизнеспособность микроглии BV-2 так и не была затронута. Однако окисленный миелин значительно изменил маркеры окислительного стресса, автофагию и метаболи

The Polyphenols α-Mangostin and Nordihydroguaiaretic Acid Induce Oxidative Stress, Cell Cycle Arrest, and Apoptosis in a Cellular Model of Medulloblastoma.

Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols α-mangostin and nordihydroguaiaretic acid (NDGA) exert potent antitumoral activity in different cancer models, although their antitumoral effects have not been described in medulloblastoma cells yet. This study aimed to examine the proapoptotic effects of these polyphenols on human medulloblastoma cells. Medulloblastoma cell line Daoy was incubated with increasing concentrations of α-mangostin or NDGA for 24 h. The cell viability was analyzed using cr

Droplet digital PCR allows vector copy number assessment and monitoring of experimental CAR T cells in murine xenograft models or approved CD19 CAR T cell-treated patients.

BACKGROUND: Genetically engineered chimeric antigen receptor (CAR) T lymphocytes are promising therapeutic tools for cancer. Four CAR T cell drugs, including tisagenlecleucel (tisa-cel) and axicabtagene-ciloleucel (axi-cel), all targeting CD19, are currently approved for treating B cell malignancies. Flow cytometry (FC) remains the standard for monitoring CAR T cells using a recombinant biotinylated target protein. Nevertheless, there is a need for additional tools, and the challenge is to develop an easy, relevant, highly sensitive, reproducible, and inexpensive detection method. Molecular to

Exosomes as a Novel Approach to Reverse Osteoporosis: A Review of the Literature.

Osteoporosis is a chronic disease requiring long-term, sometimes lifelong, management. With the aging population, the prevalence of osteoporosis is increasing, and with it so is the risk of hip fracture and subsequent poor quality of life and higher mortality. Current therapies for osteoporosis have various significant side effects limiting patient compliance and use. Recent evidence has demonstrated the significant role of exosomes in osteoporosis both in vivo and in vitro. In this review, we summarize the pathogenesis of senile osteoporosis, highlight the properties and advantages of exosome

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… Furthermore, studies have highlighted their excellent stability; PTX (Paclitaxel) incorporated into exosomes by mild sonication can maintain stability at various conditions for over a month ( Kim et al., 2016 ). Finally, their function can be enhanced through modification or material loading. …

Protosappanin B promotes apoptosis and causes G1 cell cycle arrest in human bladder cancer cells.

The aim of the study was to investigate the effects of protosappanin B on the proliferation and apoptosis of bladder cancer cells. The effects of protosappanin B (12.5, 25, 50, 100, or 200 μg/mL, 48 h) on proliferation of SV-HUC-1, T24 and 5637 cells was assessed using the MTT assay. The effects of protosappanin B (100, 150, 200, 250, or 300 μg/mL, 48 h) on cell apoptosis and cell cycle were analyzed using flow cytometry. T24 and 5637 cells treated with 200 µg/mL protosappanin B showed morphological changes (shrinkage, rounding, membrane abnormalities, and reduced adhesion), but protosappanin

Enhancement of pomalidomide anti-tumor response with ACY-241, a selective HDAC6 inhibitor.

Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies. Therefo

Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma.

Despite novel therapies, relapse of multiple myeloma (MM) is virtually inevitable. Amplification of chromosome 1q, which harbors the inflammation-responsive RNA editase adenosine deaminase acting on RNA (ADAR)1 gene, occurs in 30-50% of MM patients and portends a poor prognosis. Since adenosine-to-inosine RNA editing has recently emerged as a driver of cancer progression, genomic amplification combined with inflammatory cytokine activation of ADAR1 could stimulate MM progression and therapeutic resistance. Here, we report that high ADAR1 RNA expression correlates with reduced patient survival

The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease.

Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone di

Exosomes for angiogenesis induction in ischemic disorders.

Ischaemic disorders are leading causes of morbidity and mortality worldwide. While the current therapeutic approaches have improved life expectancy and quality of life, they are unable to "cure" ischemic diseases and instate regeneration of damaged tissues. Exosomes are a class of extracellular vesicles with an average size of 100-150 nm, secreted by many cell types and considered a potent factor of cells for paracrine effects. Since exosomes contain multiple bioactive components such as growth factors, molecular intermediates of different intracellular pathways, microRNAs and nucleic acids, t

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… i‐motif), a pH‐sensitive DNA strand enriched with cytosine, significantly promotes exosomes delivery to acidic areas, which could promote exosome targeted‐delivery to ischemia‐bearing sites. 141 In another study, hyaluronic acid grafted with 3‐diethylamino propylamine (HDEA) was loaded into exosomes via sonication … (C) Bioconjugation: Organ‐specific surface ligands, pH‐sensitive DNA strands and pro‐angiogenic miRNAs and stimulants are conjugated with exosomes through different methods including incubation, sonication and electroporation. …

Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours.

Central nervous system (CNS) tumours comprise 25% of the paediatric cancer diagnoses and are the leading cause of cancer-related death in children. Current treatments for paediatric CNS tumours are far from optimal and fail for those that relapsed or are refractory to treatment. Besides, long-term sequelae in the developing brain make it mandatory to find new innovative approaches. Chimeric antigen receptor T cell (CAR T) therapy has increased survival in patients with B-cell malignancies, but the intrinsic biological characteristics of CNS tumours hamper their success. The location, heterogen

Proteasome Inhibitors as a Possible Therapy for SARS-CoV-2.

The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug available, and therefore, current therapeutic guidelines recommend supportive care including oxygen administration and treatment with antibiotics. Recently, patients have been also treated with off-label therapies which comprise antiretrovirals, anti-inflammatory compounds, antiparasitic agents and plasma from convalescent patients, all with controversial results. The ubiquitin-proteasome system (UPS) is important for the main

Структурный анализ процесса сбора света с помощью антенн, содержащих родопсины в морской архееи Асгарда.

Акватические бактериальные редопсиновые протонные насосы собирают световую энергию для фотогетертрофного роста и, как известно, содержат гидроксилированные каротеи, расширяющие волны используемого света, но они не характеризуются морской археей. Здесь, комбинируя морскую хромофорную экстракт с очищенными архейскими родопсинами, выявленными в морских метагеномах, мы показываем передачу легкой энергии из различных гидроксилоидных каротеоидных в геймдаллархаэ (HeimdallRs) из некультурных морских планктонных членов «Candidatus Cariarachaeceae» (Candidatus Asgardarchaeota). Эти светообрабатывающие

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… The collected cells were sonicated (Ultrasonic Homogenizer VP-300N, TAITEC) for disruption in a buffer with 50 mM Tris-HCl pH 8.0 and 5 mM MgCl 2 . The membrane fraction was collected by ultracentrifugation (CP80NX, Eppendorf Himac Technologies) at 142,000 × g for 1 h. … The collected cells were disrupted by sonication in buffer containing 20 mM Tris-HCl pH 8.0, 200 mM NaCl and 10% glycerol. The crude membrane fraction was collected by ultracentrifugation at 180,000 × g for 1 h. …