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Functional cloning of the miltefosine transporter. A novel P-type phospholipid translocase from Leishmania involved in drug resistance.

The antitumor drug miltefosine (hexadecylphosphocholine, MIL) has recently been approved as the first oral agent for the treatment of visceral leishmaniasis. Little is known about the mechanisms of action and uptake of MIL in either parasites or tumor cell lines. We have cloned a putative MIL transporter (LdMT) by functional rescue, using a Leishmania donovani-resistant line defective in the inward-directed translocation of both MIL and glycerophospholipids. LdMT is a novel P-type ATPase belonging to the partially characterized aminophospholipid translocase subfamily. Resistant parasites trans

Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells.

Malignant pleural mesothelioma (MPM), an asbestos-related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in MPM treatment, overall survival of patients with MPM is very low. Recent studies have implicated that PI3K/Akt signaling is involved in MPM cell survival and development. To investigate the effects of Akt inhibitors on MPM cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti-1/2, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, and TIC10, on six MPM cell lines, namely,

Effect of PLA2G6 and SMPD1 Variants on the Lipid Metabolism in the Cerebrospinal Fluid of Patients with Parkinson's Disease: A Non-targeted Lipidomics Study.

IntroductionSleep patterns are more frequently interrupted in patients with Parkinson's disease (PD), and it is still unclear whether genetic factors are involved in PD-related sleep disorders. In this study, we hypothesize that PD-associated genetic risk affects lipid metabolism, which in turn contributes to different types of sleep disorders.MethodsWe used a non-targeted lipidomics to explore the lipid composition of cerebrospinal fluid (CSF) exosomes derived from patients with PD carrying phospholipase A2 Group VI (PLA2G6) and sphingomyelin phosphodiesterase 1 (SMPD1) mutations.ResultsPLA2G

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… Ceramide is a type of phospholipid with ceramide as the backbone, mainly including ceramide phosphorylcholine and ceramide phosphoethanolamine. Phospholipids are the main component of cell membranes, and ceramide is the main component of the intercellular matrix. …

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism.

A significant impediment to the success of cancer chemotherapy is the occurrence of multidrug resistance, which, in many cases, is attributable to overexpression of membrane transport proteins, such as the 170-kDa P-glycoprotein (P-gp). Also, upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway is known to play an important role in drug resistance, and has been implicated in the aggressiveness of a number of different cancers, including T-acute lymphoblastic leukemia (T-ALL). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine (a synt

Phage Display Derived Monoclonal Antibodies: From Bench to Bedside.

Monoclonal antibodies (mAbs) have become one of the most important classes of biopharmaceutical products, and they continue to dominate the universe of biopharmaceutical markets in terms of approval and sales. They are the most profitable single product class, where they represent six of the top ten selling drugs. At the beginning of the 1990s, an in vitro antibody selection technology known as antibody phage display was developed by John McCafferty and Sir. Gregory Winter that enabled the discovery of human antibodies for diverse applications, particularly antibody-based drugs. They created c

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… carcinoma; Aβ, Amyloid-β; FZD, Frizzled receptor; PNH, Paroxysmal nocturnal haemoglobinuria; AMD, Age-related macular degeneration; HLH, Hemophagocytic lymphohistiocytosis; MIF, Macrophage migration inhibitory factor; ICAM1, Intercellular adhesion molecule 1; oxLDL, Oxidized low-density lipoprotein; ChoP, Phosphorylcholine …

Устранение неврологических расстройств путем борьбы с нейродегенеративными ассоциированными ферментами: естественные и синтетические молекулы.

Неврологические расстройства, включая нейродегенеративные и нейро-воспалительные заболевания, создают значительные проблемы в области здравоохранения и клинических проблем. Недавние исследования показали, что различные ферменты играют ключевую роль в наступлении и развитии этих расстройств. В этом обзоре изучается терапевтический потенциал адресации этих ферментов естественными и синтетическими молекулами. К таким заболеваниям, как болезнь Альцгеймера, болезнь Паркинсона и множественный склероз, причастны основные ферменты, включая ацетилхолинестеразу, оксидазу моноамина, бета-секретазу, тау к

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… Sphingomyelinases Sphingomyelinases, enzymes that catalyze sphingomyelin hydrolysis into phosphorylcholine and ceramide, are highly prevalent in the brain. …

Recent advances in management of COVID-19: A review.

The coronavirus disease 2019 (COVID-19) pandemic caused and is still causing significant mortality and economic consequences all over the globe. As of today, there are three U.S Food and Drug administration (FDA) approved vaccines, Pfizer-BioNTech, Moderna and Janssen COVID-19 vaccine. Also, the antiviral drug remdesivir and two combinations of monoclonal antibodies are authorized for Emergency use (EUA) in certain patients. Furthermore, baricitinib was approved in Japan (April 23, 2021). Despite available vaccines and EUA, pharmacological therapy for the prevention and treatment of COVID-19 i

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… During cellular stress ASM relocates to the cell membrane, where it catalyses the cleavage of sphingomyelin into lipophilic ceramide and hydrophilic phosphorylcholine head. Ceramide is involved in cell signaling that could lead to apoptosis [90] . …

New Progress in Improving the Delivery Methods of Bisphosphonates in the Treatment of Bone Tumors.

Bone tumors are tumors that occur in the bone or its accessory tissues, including primary tumors and metastatic tumors. The main mechanism of bisphosphonate is to inhibit the resorption of destructive bone, inhibit the activity of osteoclasts and reduce the concentration of blood calcium. Therefore, bisphosphonates can be used for malignant hypercalcaemia, pain caused by osteolytic bone metastasis, prevention of osteolytic bone metastasis, multiple myeloma osteopathy, improving radiosensitivity and so on. However, the traditional administration of bisphosphonates can cause a series of adverse

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… Otaka et al 28 synthesized an amphiphilic phospholipid polymer containing ALN, namely, poly(2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate), and the polymer encapsulated docetaxel. …

The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside.

The mTOR pathway plays a central role in many cellular processes, such as cellular growth, protein synthesis, glucose, and lipid metabolism. Aberrant regulation of mTOR is a hallmark of many cancers, including hematological malignancies. mTOR inhibitors, such as Rapamycin and Rapamycin analogs (Rapalogs), have become a promising class of agents to treat malignant blood diseases-either alone or in combination with other treatment regimens. This review highlights experimental evidence underlying the molecular mechanisms of mTOR inhibitors and summarizes their evolving role in the treatment of he

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… It was designed for use as a coating in stents with phosphorylcholine as a carrier. Temsirolimus, also named 42-[3-hydroxy-2- (hydroxymethyl)-2-methylpropionate], is a Rapa derivative with molecular formula C 56 H 87 NO 16 (1030 kDa). …

Nutritional approaches in combating therapeutic resistance and enhancing treatment efficacy in cancer: the impact of ketogenic diets.

Cancer remains a major global health challenge, with therapeutic resistance significantly limiting treatment success. Traditional approaches, including surgery, chemotherapy, and radiotherapy, often encounter barriers such as metastasis and adverse effects on healthy tissues. The Warburg effect, which describes cancer cells’ reliance on glucose fermentation despite oxygen availability, has prompted investigations into alternative metabolic interventions. The ketogenic diet (KD), characterized by high fat intake and low carbohydrate intake, induces a metabolic shift that may selectively disadva

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… In contrast, temozolomide-sensitive glioblastoma cells showed elevated choline and phosphorylcholine levels compared to resistant cells [ 60 ]. Generally, increased phospholipid levels correlate with drug resistance, though exceptions exist. …

Interleukin-1 Beta-A Friend or Foe in Malignancies?

Interleukin-1 beta (IL-1β) is induced by inflammatory signals in a broad number of immune cell types. IL-1β (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of IL-1β expression and its multi-facetted role in pathophysiological conditions. IL-1 signaling activates innate immune cells including antigen presenting cells, and drives polarization of CD4+ T cells towards T helper type (Th) 1 and Th17 cells. Therefore, IL-1β has been attributed a largely beneficial

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… More recently, an alternative NLRP3-associated inflammasome pathway has been described in human monocytes which is also induced by LPS or the endogenous TLR4 ligand oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) [ 71 ]. …

Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence.

Chemoprevention is referred to as a strategy to inhibit, suppress, or reverse tumor development and progression in healthy people along with high-risk subjects and oncologic patients through using pharmacological or natural substances. Numerous phytochemicals have been widely described in the literature to possess chemopreventive properties, although their clinical usefulness remains to be defined. Among them, caryophyllane sesquiterpenes are natural compounds widely occurring in nature kingdoms, especially in plants, fungi, and marine environments. Several structures, characterized by a commo

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… Particularly, a cholesterol enrichment of a 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) biomembrane model has been reported as able to reduce the affinity binding of Pgp for adenosine triphosphate (ATP) [ 278 ]. …

Advances in nanomaterial-mediated CRISPR/Cas delivery: from lipid nanoparticles to vesicle-derived systems.

Gene and genome editing therapies are increasingly connected with nanomaterials, which protect and transport fragile nucleic acids and CRISPR/Cas systems through biological barriers safely and accurately. This review discusses how different nanocarriers, including lipid-based, polymeric, inorganic, and vesicle-derived systems, can improve delivery efficiency, cell targeting, endosomal escape, and intracellular movement for gene and genome editing. It summarizes findings from early clinical and preclinical studies, comparing several carrier types such as ionizable lipid nanoparticles, polymeric

C-Reactive Protein: Pathophysiology, Diagnosis, False Test Results and a Novel Diagnostic Algorithm for Clinicians.

The current literature provides a body of evidence on C-Reactive Protein (CRP) and its potential role in inflammation. However, most pieces of evidence are sparse and controversial. This critical state-of-the-art monography provides all the crucial data on the potential biochemical properties of the protein, along with further evidence on its potential pathobiology, both for its pentameric and monomeric forms, including information for its ligands as well as the possible function of autoantibodies against the protein. Furthermore, the current evidence on its potential utility as a biomarker of

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… CRP can bind to cholesterol, and this binding is facilitated by the phosphorylcholine-binding site of CRP and the 3beta-hydroxyl group of cholesterol [ 192 ]. …

Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familia

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… Table 5 Investigational therapeutics in ALS phase 1, 2, and 3 clinical trials involving neurotrophic factors Abbreviations: est, estimated; MPC, methacryloyloxyethyl phosphorylcholine Drug name NCT Study status | Phase | Drug category | Drug target | Drug mechanism | Additional drug mechanism(s) | Genetic …

Antibodies to watch in 2023.

In this 14th installment of the annual Antibodies to Watch article series, we discuss key events in commercial monoclonal antibody therapeutics development that occurred in 2022 and forecast events that might occur in 2023. As of mid-November, 12 antibody therapeutics had been granted first approvals in either the United States or European Union (tebentafusp (Kimmtrak), faricimab (Vabysmo), sutimlimab (Enjaymo), relatlimab (Opdualag), tixagevimab/cilgavimab (Evusheld), mosunetuzumab (Lunsumio), teclistamab (TECVAYLI), spesolimab (SPEVIGO), tremelimumab (Imjudo; combo with durvalumab), nirsevim

Экстраклектные везикли для клинической диагностики: от массовых измерений до одновидового анализа.

Экстраклектные везикулы (ЭМ) играют ключевую роль в межклеточном общении, сигнальных путях и патогенезе заболеваний, перевозя биомолекулы, такие, как ДНК, РНК, белки и липиды, полученные из клеток их происхождения, и они продемонстрировали значительный потенциал в области клинического применения. Их клиническое значение подчеркивает необходимость применения чувствительных методов для полной реализации их диагностического потенциала. В рамках этого всеобъемлющего обзора мы изучаем гетерогенность ЭМ, связанную с биогенезом, структурой, содержанием, происхождением, типом выборки и функциональными

ISEV2020 Резюме

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Четвертое Международное совещание ИСЕВ, ISEV2015.

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Резюме книги: ISEV2017.

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