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The association of Alzheimer's disease-related SNPs with mild cognitive impairment susceptibility in the Chinese population.

Previous Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD), whereas their associations with mild cognitive impairment (MCI) remain unclear. To evaluate the associations between 100 representative AD-associated SNPs and susceptibility to MCI in the Chinese population. We recruited 200 MCI patients and 200 cognitively-healthy controls from the community, matched for age and sex. Associations between SNPs and MCI risk were estimated using lasso regression, adjusted for APOE status, using different genetic models

Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus.

Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human he

Defective expression of the mu3 subunit of the AP-3 adaptor complex in the Drosophila pigmentation mutant carmine.

The adaptor protein (AP) complexes AP-1, AP-2, and AP-3 mediate coated vesicle formation and sorting of integral membrane proteins in the endocytic and late exocytic pathways in mammalian cells. A search of the Drosophila melanogaster expressed sequence tag (EST) database identified orthologs of family members mammalian medium (mu) chain families mu1, mu2, and mu3, of the corresponding AP complexes, and delta-COP, the analogous component of the coatomer (COPI) complex. The Drosophila orthologs exhibit a high degree of sequence identity to mammalian medium chain and delta-COP proteins. Northern

Fate of Antibody-Drug Conjugates in Cancer Cells.

Antibody-Drug Conjugates (ADCs) are a class of cancer therapeutics that combines antigen specificity and potent cytotoxicity in a single molecule as they are comprised of an engineered antibody linked chemically to a cytotoxic drug. Four ADCs have received approval by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) and can be prescribed for metastatic conditions while around 60 ADCs are currently enrolled in clinical trials. The efficacy of an ADC greatly relies on its intracellular trafficking and processing of its components to trigger tumor cell death. A limite

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… The clathrin dependant pathway is defined as the route ftaken up by most antigen-antibof = dy complexes. Trough this pathway, the ligand-receptor complexes cluster into pits where clathrin self assemble into lattices that drive membrane invagination. … The newly formed clathrin coated vesicles mature, losing the clathrin coat, and fuse together to form early endosomes (pH: 5.9–6). …

The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky-Pudlak syndrome and night blindness.

Lysosomes, melanosomes and platelet-dense granules are abnormal in the mouse hypopigmentation mutant pearl. The beta3A subunit of the AP-3 adaptor complex, which likely regulates protein trafficking in the trans - Golgi network/endosomal compartments, was identified as a candidate for the pearl gene by a positional/candidate cloning approach. Mutations, including a large internal tandem duplication and a deletion, were identified in two respective pearl alleles and are predicted to abrogate function of the beta3A protein. Significantly lowered expression of altered beta3A transcripts occurred

Delivery of Drugs into Cancer Cells Using Antibody-Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect.

Innumerable people worldwide die of cancer every year, although pharmaceutical therapy has actualized many benefits in human health. For background, anti-cancer drug development is difficult due to the multifactorial pathogenesis and complicated pathology of cancers. Cancer cells excrete hydrophobic low-molecular anti-cancer drugs by overexpressed efflux transporters such as multiple drug resistance 1 (MDR1) at the apical membrane. Mutation-driven drug resistance is also developed in cancer. Moreover, the poor distribution of drug to cancer cells is a serious problem, because patients suffer f

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… However, clathrin-dependent endocytosis is a predominant mechanism among a variety of endocytosis processes. … When ligands bound to their corresponding receptors on the cell surface, the clustering of ligand–receptor–AP2 (adaptor protein complex-2) complexes induced intracytoplasmic AP2–clathrin interaction and eventually formed clathrin-coated vesicles constricted by dynamin and actin. …

Эгоистические нейрофармацевтики: открытие кровеносного барьера для лечения следующего поколения.

Блокирование мозга крови (ББД) представляет собой огромную проблему в нейрофармакологии, ограничивая доставку терапевтических агентов в мозг. Экзосомы, нанокарьеры природы, стали многообещающим решением из-за их биосовместимости, низкой иммуногенности и врожденной способности пересекать ББД. Тщательное изучение анатомии и физиологии ББД свидетельствует о сложности доставки неврологических наркотиков и подчеркивает ограниченность традиционных методов. В настоящем обзоре изучается потенциал нейрофармацевтики с экзосомной силой, при этом особое внимание уделяется их структурным и функциональным с

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… Clathrin-mediated endocytosis (CME) is a major pathway facilitating exosome transcytosis across the BBB. This process relies on the formation of clathrin-coated pits that selectively engulf exosomes, allowing their intracellular trafficking and transport into the brain [ 67 ]. … Integrins play a pivotal role in exosome-mediated transport across the BBB, facilitating both receptor-mediated uptake and clathrin-independent pathways. …

Role for Reelin in neurotransmitter release.

The extracellular matrix molecule Reelin is known to control neuronal migration during development. Recent evidence suggests that it also plays a role in the maturation of postsynaptic dendrites and spines as well as in synaptic plasticity. Here, we aimed to address the question whether Reelin plays a role in presynaptic structural organization and function. Quantitative electron microscopic analysis of the number of presynaptic boutons in the stratum radiatum of hippocampal region CA1 did not reveal differences between wild-type animals and Reelin-deficient reeler mutant mice. However, additi

Role of phytoconstituents in the management of COVID-19.

BackgroundCOVID-19, a severe global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged as one of the most threatening transmissible disease. As a great threat to global public health, the development of treatment options has become vital, and a rush to find a cure has mobilized researchers globally from all areas.Scope and approachThis review focuses on deciphering the potential of different secondary metabolites from medicinal plants as therapeutic options either as inhibitors of therapeutic targets of SARS-CoV-2 or as blockers of viral particles entry

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… The most common pathway of viral internalization is clathrin mediated endocytosis as seen in the life cycles of various viruses including coronavirus [ 80 , 81 ]. … Drug chlorpromazine is used to inhibit clathrin mediated endocytosis in Ebola virus and is being tested for SARS-CoV-2 too [ 82 ]. There are several other drugs available to target cathepsin but so far, all are under clinical trials [ 83 ]. …

From Nanoparticles to Cancer Nanomedicine: Old Problems with New Solutions.

Anticancer nanomedicines have been studied over 30 years, but fewer than 10 formulations have been approved for clinical therapy today. Despite abundant options of anticancer drugs, it remains challenging to have agents specifically target cancer cells while reducing collateral toxicity to healthy tissue. Nanocompartments that can be selective toward points deeply within malignant tissues are a promising concept, but the heterogeneity of tumor tissue, inefficiency of cargo loading and releasing, and low uniformity of manufacture required from preclinical to commercialization are major obstacle

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… The nanoparticle with a larger size around 150 nm was up taken by clathrin-mediated pathway, while smaller nanoparticles of about 50 nm by clathrin-independent endocytosis [ 29 , 30 ]. … Clathrin regenerates synaptic vesicles from endosomes. Nature. 2014;515:228–233. doi: 10.1038/nature13846. 30. Hansen C.G., Nichols B.J. Molecular mechanisms of clathrin-independent endocytosis. J. Cell Sci. 2009;122:1713–1721. doi: 10.1242/jcs.033951. 31. …

Вирус Эпштейн-Барр BALF0/1 подрывает пути кавеолина и ERAD, чтобы охватить комплексы рецепторов клеток B для разложения.

Вирус Эпштейн-Барр (ЭБВ) устанавливает стойкую инфекцию, вызывает инфекционный мононуклеоз, является одним из основных пусковых факторов множественного склероза и способствует возникновению множественных раковых заболеваний. Тем не менее, знания о том, как вирус реконструирует клетки В для поддержки литического воспроизведения, остаются неполными. Ранее мы обнаружили, что EBV литическое воспроизведение приводит к избирательному истощению комплексов рецепторов клеток В (КРВ), состоящих из иммуноглобулина, а также цепочек сигнализации CD79A и CD79B. Здесь мы использовали протеомные и биохимическ

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… Caveolar and clathrin-mediated endocytosis are the two major pathways that internalize PM receptors. Clathrin pathway cargo are predominantly recycled or routed to lysosomes for degradation ( 29 ), whereas caveolar pathway cargo travel retrograde to the Golgi, ER, or to endosomes ( 30 – 34 ). … Inhibition of the clathrin endocytosis pathway by chlorpromazine ( 35 , 36 ) did not rescue BCR expression in lytic B cells ( SI Appendix , Fig. S3 A and B ). …

Ведомые АПРЕЛЬ БКМА/ТАКИ двойные целевые лиганды-наркотики для селективной и мощной терапии множественной миеломы.

Антиген созревания клеток B (BCMA) в значительной степени проявляется в злокачественных плазменных клетках и является идеальной терапевтической целью в множестве миеломы (MM). Однако эффективность лечения, ориентированного на BCMA, часто ограничивается регулированием деградации антигенов и выходом из опухоли. В этой связи мы представляем информацию о разработке двухцелевого лиганда-наркотика (НРС), использующего подпитывающий распространение лиган (АПРИЛ), естественного лиганда как для BCMA, так и для трансмембранового активатора, а также кальция-модулятора и циклофилина лиганда (TACI). Такая

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… The endocytic activity in RPMI8226 cells was significantly attenuated in the presence of clathrin inhibitors (chloroquine, chlorpromazine). … Collectively, these findings demonstrate that clathrin-mediated endocytosis and macropinocytosis are primarily involved in the receptor-mediated internalization of APRILFc. …

Targeted protein degradation: advances in drug discovery and clinical practice.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces chal

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… coat composed of clathrin, adapter proteins such as AP2 and CALM, and scaffold proteins including EPS15 and EPS15R. 225 – 227 During clathrin coat formation, cargoes are recruited to the plasma membrane. … process, dynamin assembles the ‘nick’ of clathrin-coated pit. 225 Dynamin then mediates membrane fission, a process driven by GTP hydrolysis. …

Opportunities and Challenges in Antibody-Drug Conjugates for Cancer Therapy: A New Era for Cancer Treatment.

The antibody, linker, and payload moieties all play a significant role in giving the ADC its unique therapeutic potential. The antibody subclass employed in ADCs is determined based on relative individual receptor affinities and pharmacokinetics. Meanwhile, the linker used in an ADC can either be cleavable or non-cleavable. ADC therapy comprises antibody-dependent mechanisms in addition to the direct cytotoxic effects of the payload. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, as well as the "bystander

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… While the internalization most commonly occurs via clathrin-mediated endocytosis, there are ongoing efforts to engineer the antibodies to exploit the endolysosomal systems [ 52 ]. … One study showed that using tetravalent antibodies instead of bivalent antibodies, along with FGFR1 receptor clustering, could induce fast and efficient uptake that can occur via both clathrin-dependent and dynamin-mediated clathrin-independent mechanisms [ 85 ]. …

A review on the current literature regarding the value of exosome miRNAs in various diseases.

Exosome microRNAs (miRNAs) have great research outlook in clinical therapy and biomarkers, they have been found to have a close to multiple diseases. A growing number of studies have attempted to alleviate or treat diseases through exosomes. It indicates that miRNAs in exosomes have great significance in preventing and controlling diseases in clinical research. We summarise these studies below to better understand their implications.We screened and analyzed more than 100 articles from PubMed, Web of Science, and other databases from 1987 to 2022. Data of the clinical trials are collected from

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… Clathrin is a highly conserved protein, which mainly plays a major role in transport in the human body. Exosome miR-214 from ADRCs has been proven to inhibit cell death through clathrin endocytosis and reduce the risk of heart rupture in acute myocardial infarction [ 43 ]. … Cardiomyocytes capture stem cell-derived, anti-apoptotic microRNA-214 via clathrin-mediated endocytosis in acute myocardial infarction. J Biol Chem. 2019;294(31):11665–11674. doi: 10.1074/jbc.RA119.007537. 44. Ma T, Chen Y, Chen Y, et al. …

Полиморфизм меланкортина - генезиалы с воспалением и болезнями.

Рецепторы Меланокортина (МКР) выполняют различные функции: от пигментации кожи, регулирования аппетита, реакции на стресс и когниции, синтеза стероидов и энергетического баланса до регенерации клеток и иммуномодуляции. Генетический полиморфизм с распределением тканей от мозга, лимбической системы и адренальной коры до нейтрофилов, моноцитов и макрофазов проявляется в MCR. Мутации в генах MC1R, MC2R, MC3R и MC4R связаны с риском меланомы, семейной глюкокортикоидной недостаточности, ожирения и типа 2 Диафиозный сахар, соответственно. Тем временем, MC1R, MC2R и MC5R связаны с риском серьезного де

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… Clathrin-coated-pits (CCPs) play an important role in receptor desensitization. β-arrestins recruit the clathrin molecules to form CCPs. Desensitization of GPCR is usually followed by receptor internalization and downregulation. … trisphosphate CREB Cyclic AMP response element binding protein JAK/STAT Janus kinase (JAK), signal transducer and activator of transcription protein (STAT) PDZ domain Postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (DlgA), and zonula occludens-1 protein (zo-1) domain CCP Clathrin-coated-pit …

Antibody-drug conjugates in cancer therapy: mechanisms and clinical studies.

Antibody-drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies' targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored

Механизм поглощения и токсичности антителного препарата BCMA в сочетании с полезной нагрузкой MMAF неантигенными функционирующими элементами.

Belantamab mafodotin, антитело-наркомания (ADC), продемонстрировал высокую эффективность в множестве миеломы. Он состоит из гуманизированного антиклектового антигена (BCMA) IgG1 моноклонального антитела, смешанного с монометил-ауристатином F (MMAF) с помощью манимидокапроилового связующего устройства. С помощью неизвестных механизмов поступили сообщения о связанных с окультизмом неблагоприятных явлениях, в частности о роговицах, в которых содержится АКЦ, в том числе белантамб мафодотин. В ходе этого исследования изучался механизм поглощения и цитотоксичности белантамбом мафодотином, содержащим

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… HCEC treated with siRNA, including siAP2mu2 (marker for clathrin-mediated endocytosis) and siCDC42 (involved in fluid phase endocytosis pathways), were incubated with Vivotag680-labeled ADC, mAb, transferrin-Alexa647, and dextran, and uptake was analyzed by flow cytometry (excluding ADC). … Co-treatment with nystatin or chlorpromazine, which target the caveolin and clathrin endocytic pathways, respectively, reduced ADC uptake into HCEC by approximately 20%, and nystatin reduced ADC-mediated cytotoxicity as measured by nuclei count. …

Repurposing anticancer drugs for the management of COVID-19.

Since its outbreak in the last December, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread worldwide at a pandemic proportion and thus is regarded as a global public health emergency. The existing therapeutic options for COVID-19 beyond the intensive supportive care are limited, with an undefined or modest efficacy reported so far. Drug repurposing represents an enthusiastic mechanism to use approved drugs outside the scope of their original indication and accelerate the discovery of new therapeutic options. With the emergence of COVID-19, drug repurposing has been la

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… The virus dissembles and releases its nucleocapsid and RNA material into the host cell cytoplasm via caveolae- and clathrin-mediated endocytosis [ 215 ]. … This pathway involves phosphatidylinositol binding clathrin assembly protein (PICALM), which is a cargo-selecting clathrin adaptor that drives membrane curvature during endocytosis [ 90 , 119 ]. …

The potential role of cannabidiol (CBD) in lung cancer therapy: a systematic review of preclinical and clinical evidence.

BackgroundLung cancer is one of the most prevalent and lethal cancers worldwide, with limited therapeutic options in advanced stages. Cannabinoids have recently attracted attention as potential anticancer agents; however, cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, has emerged as the most promising candidate. Unlike Δ9-tetrahydrocannabinol (THC), CBD lacks psychoactive properties, is generally well tolerated, and demonstrates a favorable safety profile. Moreover, CBD influences multiple cancer-relevant pathways-including apoptosis, epithelial-to-mesenchymal tra

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… . - CBD upregulates E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101. - CBD decreases intracellular ATP and glucose levels. … PPARy-dependent vesicle formation; Regulation of apoptotic pathways; ATP and glucose metabolism disruption PPARy, clathrin, β-adaptin, RIP1/RIP3 [ 26 ] Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8 + T and NK cells 2023 In vivo …