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Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies.

Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD+ production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., FK866 (APO866)) in preclinical studies, their clinical activity was proven to be limited. Here, we report the synthesis of new NAMPT Inhibitors, JJ08, FEI191 and FEI199, which exhibit a broad anticancer activity in vitro. Results show that these compounds are potent NAMPT inhibito

Role of Long Non-Coding RNA X-Inactive-Specific Transcript (XIST) in Neuroinflammation and Myelination: Insights from Cerebral Organoids and Implications for Multiple Sclerosis.

Background/Objectives: X-inactive-specific transcript (XIST) is a factor that plays a role in neuroinflammation. This study investigated the role of XIST in neuronal development, neuroinflammation, myelination, and therapeutic responses within cerebral organoids in the context of Multiple Sclerosis (MS) pathogenesis. Methods: Human cerebral organoids with oligodendrocytes were produced from XIST-silenced H9 cells, and the mature organoids were subsequently treated with either FTY720 or DMF. Gene expression related to inflammation and myelination was subsequently analyzed via qRT-PCR. Immunoflu

B7-H3 (CD276) as Target for T Cell-Based Bispecific Antibody Therapy of Penile Cancer.

IntroductionMetastatic or locally advanced penile cancer (PeCa) has limited systemic treatment options and a 5-year survival rate of ~10% in metastatic disease. Using the in vitro and ex vivo models we preclinically assessed CC-3, a B7-H3xCD3 bispecific antibody (bsAb) currently in a Phase I basket trial (NCT05999396).MethodsPrimary PeCa cells were isolated from surgical specimens and characterized for surface antigen expression by flow cytometry (n = 4). B7-H3 expression was additionally evaluated in primary penile cancer tissues by immunohistochemistry (n = 10). The functional activity of th

Target inhibition of SPAK in choroid plexus attenuates T cell infiltration and demyelination in experimental autoimmune encephalomyelitis.

BACKGROUND: Disease-modifying therapies (DMTs) that prevent immune cell infiltration into the brain have demonstrated efficacy in multiple sclerosis (MS) treatment. However, their unpredictable adverse effects necessitate the development of safer therapeutic alternatives. The choroid plexus (ChP) functions as a crucial barrier against immune cell invasion, and previous studies have shown that preventing immune cell infiltration across the ChP reduces brain lesion in MS animal models. Understanding ChP barrier regulation is therefore essential for identifying novel therapeutic targets for MS. H

VP3.15, двойной ингибитор GSK-3β/PDE7, уменьшает рост опухоли глиобластомы, изменяя микроопухоль в контексте PTEN дикой природы.

Глиобластома (ГБ) — неизлечимый рак мозга, и необходимо срочно определить эффективные методы лечения. Это может быть достигнуто либо путем идентификации новых молекул, либо путем переочистки наркотиков. Для определения терапевтического потенциала известных ингибиторов GSK-3β и/или PDE7 в GB был проведен анализ наркотиков с использованием модели глиомы Дрософила меланогастера. VP3.15, двойной ингибитор с противовоспалительными и нейрозащитными функциями при множественном склерозе, был выбран для дальнейшего изучения. VP3.15 продемонстрировал высокую антиопухоль против панели клеток человека и м

Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect.

Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. We investigated possible BTZ and CFZ off-targets able to explain their different neurotoxicity profiles. In order to identify the possible PIs off-targets we used the SPILLO-PBSS software that performs a structure-base

Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis.

Non-native immunoglobulin light chain conformations, including aggregates, appear to cause light chain amyloidosis pathology. Despite significant progress in pharmacological eradication of the neoplastic plasma cells that secrete these light chains, in many patients impaired organ function remains. The impairment is apparently due to a subset of resistant plasma cells that continue to secrete misfolding-prone light chains. These light chains are susceptible to the proteolytic cleavage that may enable light chain aggregation. We propose that small molecules that preferentially bind to the nativ

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… Release of fluorophore-labeled peptides by aberrant proteolysis was quantified by fluorescence polarization. … From a library of over 650,000 small molecules, this so-called “protease-coupled fluorescence polarization” assay identified multiple small molecule stabilizer hits that reduced the decrease in fluorescence polarization. These stabilizers were validated using a series of counter screens. …

Sp3 улучшила экспериментальный аутоиммунный энцефаломиэлит, спровоцировав Socs3 в клетках Th17.

ВВЕДЕНИЕ: Хотя считается, что хронические подстрекательские и дегенеративные заболевания центральной нервной системы поддерживаются аутоиммунными клетками ТТ17, основополагающие механизмы остаются в основном неисследованными. Недавние исследования и наши исследования показали, что Sp3 был заблокирован в нескольких склерозах (MS) и экспериментальном аутоиммунном энцефаломиелите (EAE). Вместе с тем остается неясным, почему в нем ничего не говорится и как он регулирует дифференциацию клеток TH17 в MS. ЦЕЛИ: Данное исследование было направлено на изучение воздействия Сп3 на ТХ17 в клетках EAE и ле

Covalent targeting of PSMD14 by Eupalinolide B induces oncoprotein degradation and apoptosis in acute promyelocytic leukemia cells.

Treatment of acute promyelocytic leukemia (APL) remains challenged by toxicities associated with current regimens, highlighting the need for novel and safer therapeutic agents. Here, we identify Eupalinolide B (EB), a natural sesquiterpene lactone isolated from Eupatorium lindleyanum DC., as a potent anti-leukemic compound targeting the human APL-derived HL-60 cell line. Through integrated chemoproteomic profiling and functional validation, we demonstrate that EB covalently binds and inhibits 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a deubiquitinase enzyme (DUB) within the 19S

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… In vitro PSMD14 activity assay PSMD14 activity was assessed using fluorescence polarization measurements in black 96-well microplates. The reaction buffer contained 50 μM ATP, 50 mM Tris–HCl (pH 7.5), 0.01% NP-40, 1 mM MgCl 2 and 1 mM DTT. … Fluorescence polarization was measured at 30 °C using an EnVision 2105 Multimode Plate Reader. Transfection assay Duplex small interfering RNAs (siRNAs) targeting PSMD14 and a negative control (siNC) were chemically synthesized by GENERAY (Shanghai, China). …

Mesenchymal stem cells lineage and their role in disease development.

BackgroundMesenchymal stem cells (MSCs) are widely dispersed in vivo and are isolated from several tissues, including bone marrow, heart, body fluids, skin, and perinatal tissues. Bone marrow MSCs have a multidirectional differentiation potential, which can be induced to differentiate the medium in a specific direction or by adding specific regulatory factors. MSCs repair damaged tissues through lineage differentiation, and the ex vivo transplantation of bone marrow MSCs can heal injured sites. MSCs have different propensities for lineage differentiation and pathological evolution for differen

Известная эволюция полимер-связывающего пептида LCI для улучшения связывания полипропилена.

Функционализация поверхностей полимеров с помощью полимерных связывающих пептидов предоставляет значительные возможности для направленногоImmobilization ферментов, биоактивных пептидов и антигенов. Применение полимерных связывающих пептидов в качестве адгезивов требует надежного и стабильного связывания при условиях процесса. Молекулярные режимы взаимодействия между материалами поверхностей, пептидами и растворителем часто не понимаются на уровне, который позволяет (semi-) рационально проектировать полимерные связывающие пептиды, что мешает полному использованию их потенциала. Концепция направ

Биарил Фосфаты и фосфонаты как выборочные ингибаторы фактора транскрипции СТАТ4.

Коэффициент транскрипции STAT4 был связан с патогенезом аутоиммунных заболеваний, включая провокационное заболевание кишечника, множественный склероз, ревматоидный артрит и сахарный диабет. Здесь мы представляем P-biaryl фосфаты и фосфонаты в качестве первых малых ингибиторов СТАТ4. Наиболее мощный фосфат P-biaryl интенсифицировал домен взаимодействия белка и протеина STAT4, домен SH2, с субмикромолической пользой (Ki = 0,35 мкМ) и 14-кратной избирательностью по близкому члену семьи STAT3, который имеет тот же основной пептид, что и STAT4. Дальнейшая разработка привела к созданию ингибитора, у

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… Here, we report para ‐biphenyl phosphate ( 1 , Figure  1a ) as a selective inhibitor of the SH2 domain of STAT4 ( K i  = 1.1 ± 0.1 µM) in fluorescence polarization (FP) assays (Figure  1b ; Tables  1 , S1 and S2 ). …

A distinct CAR-T cell phenotype mediates therapeutic response at limited doses.

Chimeric antigen receptor (CAR) T-cell therapies are typically administered at high doses to maximize durable clinical responses. However, manufacturing constraints can limit the production of sufficient cells to achieve the intended dose. Although some patients experience durable responses after receiving lower CAR-T cell doses, the mechanisms underlying efficacy at these limited cell numbers remain poorly understood. To address this, we performed deep phenotyping of anti-CD19 CAR-T cell products and their corresponding leukapheresis starting materials from a phase I/II dose-escalation trial.

Total disc replacement using a tissue-engineered intervertebral disc in vivo: new animal model and initial results.

STUDY TYPE: Basic science Introduction:  Chronic back pain due to degenerative disc disease (DDD) is among the most important medical conditions causing morbidity and significant health care costs. Surgical treatment options include disc replacement or fusion surgery, but are associated with significant short- and long-term risks.1 Biological tissue-engineering of human intervertebral discs (IVD) could offer an important alternative.2 Recent in vitro data from our group have shown successful engineering and growth of ovine intervertebral disc composites with circumferentially aligned collagen

Effects of pegylated G-CSF on immune cell number and function in patients with gynecological malignancies.

BackgroundPegylated granulocyte colony-stimulating factor (G-CSF; pegfilgrastim) is a longer-acting form of G-CSF, whose effects on dendritic cell (DC) and regulatory T cell (Treg) mobilization, and on the in vivo and ex vivo release of immune modulating cytokines remain unexplored.MethodsTwelve patients with gynecological cancers received carboplatin/paclitaxel chemotherapy and single-dose pegfilgrastim as prophylaxis of febrile neutropenia. Peripheral blood was collected prior to pegfilgrastim administration (day 0) and on days +7, +11 and +21, to quantify immunoregulatory cytokines and to a

Therapeutic siRNAs Targeting the JAK/STAT Signalling Pathway in Inflammatory Bowel Diseases.

Background and aimsInflammatory bowel diseases are highly debilitating conditions that require constant monitoring and life-long medication. Current treatments are focused on systemic administration of immunomodulatory drugs, but they have a broad range of undesirable side-effects. RNA interference is a highly specific endogenous mechanism that regulates the expression of the gene at the transcript level, which can be repurposed using exogenous short interfering RNA [siRNA] to repress expression of the target gene. While siRNA therapeutics can offer an alternative to existing therapies, with a

The Fifth International Meeting of ISEV, ISEV2016, Rotterdam, The Netherlands, 4 - 7 May, 2016.

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Искусственные интеллектуальные технологии зондирования для борьбы с раком, диабетом и COVID-19.

Интеграция искусственного интеллекта (АИ) с износимыми сенсорными технологиями может привести к революции в мониторинге и лечении различных хронических заболеваний и острых заболеваний. Комбинированные износы АИ классифицируются по таким основополагающим методам зондирования, как электрохимическая, колориметрическая, химическая, оптическая, а также давление/стабильность. Алгоритмы АИ повышают эффективность изношенных датчиков, обеспечивая индивидуализированный, постоянный надзор и прогнозный анализ, помогая распознавать время и оптимизируя терапевтические методы. В этой рукописи рассматриваютс

The progress and perspective of nanomedicine in modulating the tumor immune microenvironment.

The widespread application of nanomedicine in oncology is reshaping cancer treatment paradigms. Using the precise targeting mechanisms and the rapid advancements in nanoscale materials, nanomedicine is driving progress in cancer therapy, particularly within the complex landscape of the tumor immune microenvironment (TIM). This review provides a comprehensive overview of recent studies elucidating the critical role of nanomedicine in modulating the TIM, augmenting the efficacy of immunotherapies, and overcoming therapeutic resistance. Emphasis is placed on the significance of targeted drug deli

Структурное и механистическое профилирование модулятуры Hurr1 vidofludimus позволяет проектировать лиганд на основе структуры.

В центре биомедицинских исследований находится фактор нейрозащиты, связанный с ядерным рецептором 1 (Nurr1, NR4A2) для его многообещающей нейрозащитной роли в болезни Паркинсона, болезни Альцгеймера и множественном склерозе. Его деятельность может контролироваться лигандами, предлагающими доступ к фармакологической модуляции Hurr1. Вместе с тем связующие эпитопы и механизмы молекулярной активации синтетических активаторов Hurr1 по-прежнему остаются труднодостижимыми, но имеют важное значение для продвижения к новым лекарствам лигандов Hurr1. Здесь мы охарактеризовали диссоциацию Hurr1 димера и