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XRK3F2 Inhibition of p62-ZZ Domain Signaling Rescues Myeloma-Induced GFI1-Driven Epigenetic Repression of the Runx2 Gene in Pre-osteoblasts to Overcome Differentiation Suppression.

Multiple myeloma bone disease (MMBD) is characterized by non-healing lytic bone lesions that persist even after a patient has achieved a hematologic remission. We previously reported that p62 (sequestosome-1) in bone marrow stromal cells (BMSC) is critical for the formation of MM-induced signaling complexes that mediate OB suppression. Importantly, XRK3F2, an inhibitor of the p62-ZZ domain, blunted MM-induced Runx2 suppression in vitro, and induced new bone formation and remodeling in the presence of tumor in vivo. Additionally, we reported that MM cells induce the formation of repressive chro

Оптимизированная внутриназальная доставка сегестерона ацетатата в мозг с использованием наноэмульсии и микроэмульсии.

Segesteron aцетат (SA) является селективным и мощным агонистом рецептора прогестерона с потенциальным применением в лечении неврологических заболеваний, таких, как множественный склероз и инсульт. В этом исследовании микроэмульсия (МЭ) и three Наноэмульсии (NEs) с целевой концентрацией SA 0.48 Мг/г были разработаны для интраназального администрирования и подробно описаны в отношении их физико-химических свойств, устойчивости, антимикробной активности и безопасности (на первичных кортикальных клетках, тесте на яйцеклетки Hen/s, модели MucilAirTM и на крысах). Измерялись уровни плазмы и SA мозга

CXCL13 Повреждает позвоночник крови, поощряя RNF6/Sqstm1-Ubictiination.

Повреждение позвоночника крови (BSCB) приводит к нарушению иммунной микроокружающей среды в центральной нервной системе во время развития множественного склероза (MS) и экспериментального аллергического энцефаломиэлита (EAE). Тем не менее основные механизмы, связанные с повреждением барьера, по-прежнему недостаточно изучены. Здесь, анализируя белковые профили в периферической сыворотке крови, хемокин (C-X-C motif) Ligand 13 (CXCL13) был определен как возрастающий по мере развития MS и EAE. Отсутствие CXCL13 привело к снижению симптомов EAE, о чем свидетельствует сокращение числа клинических оц

miR‑140‑5p inhibits the proliferation of multiple myeloma cells by targeting VEGFA.

MicroRNA (miR)‑140‑5p is associated with the growth and metastasis of various tumor cell types, yet its role in multiple myeloma (MM) remains unclear. Therefore, the present study aimed to investigate the regulatory effect of miR‑140‑5p on MM. Reverse transcription‑quantitative PCR analysis demonstrated that miR‑140‑5p was downregulated in MM cell lines, particularly in U266 and RPMI 8226 cells. A Cell Counting Kit‑8, wound healing and Transwell assays, as well as flow cytometry indicated that a miR‑140‑5p mimic could suppress cell viability, migration and invasion. In addition, the mimic prom

Combination of MCL-1 and BCL-2 inhibitors is a promising approach for a host-directed therapy for tuberculosis.

Tuberculosis (TB) accounts for 1.6 million deaths annually and over 25% of deaths due to antimicrobial resistance. Mycobacterium tuberculosis (M.tb) drives MCL-1 expression (family member of anti-apoptotic BCL-2 proteins) to limit apoptosis and grow intracellularly in human macrophages. The feasibility of re-purposing specific MCL-1 and BCL-2 inhibitors to limit M.tb growth, using inhibitors that are in clinical trials and FDA-approved for cancer treatment has not be tested previously. We show that specifically inhibiting MCL-1 and BCL-2 induces apoptosis of M.tb-infected macrophages, and mark

Нейроинфламмация вызывает митральную дисфункцию клеток и обонятельное расстройство в множественной склерозовой модели.

Олокационная дисфункция является недооцененным симптомом множественного склероза (МС). Здесь мы изучили патогенные механизмы, лежащие в основе вызванной воспалением дисфункции обонятельной луковицы, используя животную модель MS, экспериментальный аутоиммунный энцефаломиелит (EAE). Результаты: Сокращенная обонятельная функция в EAE была связана с дегенерацией короткоаксоновых нейронов, незрелых нейронов, а также как митральных, так и тушёных клеток наряду с их синаптическим взаимодействием и аксонным репертуаром. Чтобы расчленить механизмы, лежащие в основе восприимчивости митральных клеток, гл

Nanotherapeutics in the EU: an overview on current state and future directions.

The application of nanotechnology in areas of drug delivery and therapy (ie, nanotherapeutics) is envisioned to have a great impact on public health. The ability of nanotherapeutics to provide targeted drug delivery, improve drug solubility, extend drug half-life, improve a drug's therapeutic index, and reduce a drug's immunogenicity has resulted in the potential to revolutionize the treatment of many diseases. In this paper, we review the liposome-, nanocrystal-, virosome-, polymer therapeutic-, nanoemulsion-, and nanoparticle-based approaches to nanotherapeutics, which represent the most suc

Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 M

Translational strategy to support the first-in-human study of a TCR-like T cell bispecific with an in vitro-based safety approach.

The nonclinical development of T-cell receptor (TCR)-based therapeutics is uniquely challenged by the human-exclusive specificity of the peptide-HLA target, rendering conventional animal models unsuitable for safety assessment. To support first-in-human (FIH) studies in patients with solid tumors with the novel TCR-like T Cell Bispecific (TCB) antibody MAGE-A4-TCB, targeting the MAGE-A4 peptide presented by HLA-A*02:01 and engaging T-cells via the CD3ϵ chain, we implemented a comprehensive, prediction-independent safety strategy relying on New Approach Methodologies (NAMs). This approach utili

Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells.

Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia, on Gefitinib-resistant NSCLC cell lines in vitro and in vivo. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with

Microorganisms Associated with the Marine Sponge Scopalina hapalia: A Reservoir of Bioactive Molecules to Slow Down the Aging Process.

Aging research aims at developing therapies that delay normal aging processes and some related pathologies. Recently, many compounds and extracts from natural products have been shown to slow aging and/or extend lifespan. Marine sponges and their associated microorganisms have been found to produce a wide variety of bioactive secondary metabolites; however, those from the Southwest of the Indian Ocean are much less studied, especially regarding anti-aging activities. In this study, the microbial diversity of the marine sponge Scopalina hapalia was investigated by metagenomic analysis. Twenty-s

Study of the role of transmembrane emp24 domain-containing protein 2 in oral squamous cell carcinoma.

ObjectiveThis study aimed to investigate the role of transmembrane emp24 domain-containing protein 2 (TMED2) in oral squamous cell carcinoma (OSCC).MethodologyA bioinformatics analysis was first conducted to explore TMED2 expression in OSCC and its relation with overall survival. The analysis results were further verified by assessing TMED2 expression levels in human normal oral keratinocyte cells and human OSCC cell lines using quantitative real-time polymerase chain reaction and the Western blot. Finally, the effects of TMED2 knockdown and overexpression on the expression levels of TMED2, AD

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

BackgroundMCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902).MethodsBinding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xen

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, sensitizes lung cancer cells to treatment with epidermal growth factor receptor tyrosine kinase inhibitors.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge to targeted therapy for non-small cell lung cancer (NSCLC). We investigated whether a cyclin D kinase 4/6 (CDK4/6) inhibitor, PD 0332991, could reverse EGFR-TKI resistance in human lung cancer cells and explored the underlying mechanisms. We found that PD 0332991 potentiated gefitinib-induced growth inhibition in both EGFR-TKI-sensitive (PC-9) and EGFR-TKI-resistant (PC-9/AB2) cells by down-regulating proliferation and inducing apoptosis and G0/G1 cell cycle arrest. Tumor xenogra

Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN).

Chemotherapy induced peripheral neuropathy (CIPN) is a type of neuropathic pain that is a major dose-limiting side-effect of potentially curative cancer chemotherapy treatment regimens that develops in a "stocking and glove" distribution. When pain is severe, a change to less effective chemotherapy agents may be required, or patients may choose to discontinue treatment. Medications used to alleviate CIPN often lack efficacy and/or have unacceptable side-effects. Hence the unmet medical need for novel analgesics for relief of this painful condition has driven establishment of rodent models of C

Совпадение в полном тексте источника
… -1 receptor attenuate CIPN | Nieto et al., 2012 Oxaliplatin | Patients | Integrin beta-3 L33P is related to CIPN severity but not the development of CIPN | Antonacopoulou et al., 2010 Paclitaxel | Male SD rats | Inflammation | Alaedini et al., 2008 ; Wang et al., 2012 Cisplatin Taxol | Balb/c mice | … Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice . J. Pain 13 , 1107 – 1121 10.1016/j.jpain.2012.08.006 23063344 Norcini M. Vivoli E. Galeotti N. Bianchi E. Bartolini A. Ghelardini C. ( 2009 ). Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat . …

Açai Berry Attenuates Cyclophosphamide-Induced Damage in Genitourinary Axis-Modulating Nrf-2/HO-1 Pathways.

Cyclophosphamide (CYP) is used to treat different malignancies and autoimmune disorders in men. This chemotherapy frequently reduces tumors, which is beneficial, but also causes infertility because of severe oxidative stress, inflammation, and apoptosis in the bladder and testes brought on by its metabolite, acrolein. The goal of this study was to assess the efficacy of a novel food, açai berry, in preventing CYP-induced damage in the bladder and testes.MethodsCYP was administered intraperitoneally once during the experiment at a dose of 200 mg/kg body weight diluted in 10 mL/kg b.w. of water.

Biological Evaluation of Naproxen-Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors.

The use of peptide-drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen-dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition

SFRP5 inhibits melanin synthesis of melanocytes in vitiligo by suppressing the Wnt/β-catenin signaling.

Secreted frizzled-related protein 5 (SFRP5) plays a pivotal role in regulating the development of many tissues and organs, however, as an inhibitor of Wnt signaling, the role of SFRP5 in vitiligo remains unknown. Hence, we speculated that SFRP5 might be associated with melanogenesis in melanocytes by regulating Wnt signaling in vitiligo. In this study, we found that SFRP5 was overexpressed in the skin lesions of patients with vitiligo. Compared with that in normal epidermal melanocytes (PIG1), the expression of SFRP5 was increased in vitiligo melanocytes (PIG3V). To investigate the effect of S

Porphyromonas gingivalis усугубляет экспериментальный аутоиммунный энцефаломиэлит, проводя дифференциацию TH1 с помощью сигнала ZAP70/NF-IB.

Множественный склероз (MS) характеризуется хроническим воспалением и обезвоживанием в центральной нервной системе (CNS), главным образом в результате ненормальной активации периферической иммунной системы, в частности клеток TH1. Как основной патоген в периодонтрите, Porphyromonas gingivalis (P. gingivalis) связан с повышенным риском множественных склерозных прогрессий; однако его роль в центральной нервной системе воспаления остается неясной. В этом исследовании мы стремились определить, поощряет ли P. gingivalis периферическую дифференциацию клеток TH1 по сигнальному маршруту ZAP70/NF-InB, т

Parasites' immunomodulators: a breakthrough in immunotherapeutics displaying antineoplastic activity against human colorectal and hepatocellular carcinoma cells.

The complex interplay between parasites and cancer is yielding promising advances in the field of cancer therapeutics. This study explored the in vitro anti-cancer potential of parasite immunomodulators (antigens and antibodies) of Schistosoma mansoni, Trichinella spiralis, and Toxoplasma gondii on human HT-29 colorectal and HepG2 hepatocellular carcinoma cells using the MTT assay. Results revealed that those parasites' immunomodulators exhibited antineoplastic activity and demonstrated a statistically significant inhibition of both cancer cell lines' proliferation (P ˂0.05). Notably, Trichine