bims-meglyc 2022-12-11 papers

on Metabolic disorders affecting glycosylation

Issue of 2022–12–11
twenty-one papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Small molecule inhibitors of mammalian glycosylation.
Glycobiology of cellular expiry: decrypting the role of glycan-lectin regulatory complex and therapeutic strategies focusing on cancer.
Inosine: A bioactive metabolite with multimodal actions in human diseases.
Current and new therapies for mucopolysaccharidoses.
Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis.
Glutamine metabolism and radiosensitivity: Beyond the Warburg effect.
Targeting glycolysis for cancer therapy using drug delivery systems.
Hallmarks of cancer: The insulin-like growth factors perspective.
Fatty acid transport proteins (FATPs) in cancer.
Functional regulation of Wnt protein through post-translational modifications.
Phosphatidylserine in Diabetes Research.
Autophagy: An important target for natural products in the treatment of bone metabolic diseases.
Proximity labeling technologies to illuminate glycan-protein interactions.
CNS and CNS diseases in relation to their immune system.
CRISPR screens for functional interrogation of immunity.
Targeting redox regulation and autophagy systems in cancer stem cells.
The Growth Factors: Potential Biomarkers and Therapeutic Targets in Kidney Diseases.
Pseudo-glycoconjugates with a C-glycoside linkage.
Multiplexed engineering and precision gene editing in cellular immunotherapy.
Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage.
Extracellular matrix in Skin Diseases: the road to new therapies.

Matrix Biol Plus. 2022 Dec;16 100108

Small molecule inhibitors of mammalian glycosylation.

Karim Almahayni, Malte Spiekermann, Antonio Fiore, Guoqiang Yu, Kayvon Pedram, Leonhard Möckl.

  Glycans are one of the fundamental biopolymers encountered in living systems. Compared to polynucleotide and polypeptide biosynthesis, polysaccharide biosynthesis is a uniquely combinatorial process to which interdependent enzymes with seemingly broad specificities contribute. The resulting intracellular cell surface, and secreted glycans play key roles in health and disease, from embryogenesis to cancer progression. The study and modulation of glycans in cell and organismal biology is aided by small molecule inhibitors of the enzymes involved in glycan biosynthesis. In this review, we survey the arsenal of currently available inhibitors, focusing on agents which have been independently validated in diverse systems. We highlight the utility of these inhibitors and drawbacks to their use, emphasizing the need for innovation for basic research as well as for therapeutic applications.

Keywords:  Glycans; Glycocalyx; Glycosylation; Inhibitors; Small molecules

DOI:  https://doi.org/10.1016/j.mbplus.2022.100108
Biochem Pharmacol. 2022 Dec 05. pii: S0006-2952(22)00462-2. [Epub ahead of print] 115367

Glycobiology of cellular expiry: decrypting the role of glycan-lectin regulatory complex and therapeutic strategies focusing on cancer.

Abhishek Kumar Das, Noyel Ghosh, Ankita Mandal, Parames C Sil.

  Often the outer leaflets of living cells bear a coat of glycosylated proteins, which primarily regulates cellular processes. Glycosylation of such proteins occurs as part of their post-translational modification. Within the endoplasmic reticulum, glycosylation enables the attachment of specific oligosaccharide moieties such as, 'glycan' to the transmembrane receptor proteins which confers precise biological information for governing the cell fate. The nature and degree of glycosylation of cell surface receptors are regulated by a bunch of glycosyl transferases and glycosidases which fine-tune attachment or detachment of glycan moieties. In classical death receptors, upregulation of glycosylation by glycosyl transferases is capable of inducing cell death in T cells, tumor cells, etc. Thus, any deregulated alternation at surface glycosylation of these death receptors can result in life-threatening disorder like cancer. In addition, transmembrane glycoproteins and lectin receptors can transduce intracellular signals for cell death execution. Exogenous interaction of lectins with glycan containing death receptors signals for cell death initiation by modulating downstream signalings. Subsequently, endogenous glycan-lectin interplay aids in the customization and implementation of the cell death program. Lastly, the glycan-lectin recognition system dictates the removal of apoptotic cells by sending accurate signals to the extracellular milieu. Since glycosylation has proven to be a biomarker of cellular death and disease progression; glycans serve as specific therapeutic targets of cancers. In this context, we are reviewing the molecular mechanisms of the glycan-lectin regulatory network as an integral part of cell death machinery in cancer to target them for successful therapeutic and clinical approaches.

Keywords:  Apoptosis; Autophagy; Cell death; Glycan; Lectin

DOI:  https://doi.org/10.1016/j.bcp.2022.115367
Front Pharmacol. 2022 ;13 1043970

Inosine: A bioactive metabolite with multimodal actions in human diseases.

In Soo Kim, Eun-Kyoung Jo.

  The nucleoside inosine is an essential metabolite for purine biosynthesis and degradation; it also acts as a bioactive molecule that regulates RNA editing, metabolic enzyme activity, and signaling pathways. As a result, inosine is emerging as a highly versatile bioactive compound and second messenger of signal transduction in cells with diverse functional abilities in different pathological states. Gut microbiota remodeling is closely associated with human disease pathogenesis and responses to dietary and medical supplementation. Recent studies have revealed a critical link between inosine and gut microbiota impacting anti-tumor, anti-inflammatory, and antimicrobial responses in a context-dependent manner. In this review, we summarize the latest progress in our understanding of the mechanistic function of inosine, to unravel its immunomodulatory actions in pathological settings such as cancer, infection, inflammation, and cardiovascular and neurological diseases. We also highlight the role of gut microbiota in connection with inosine metabolism in different pathophysiological conditions. A more thorough understanding of the mechanistic roles of inosine and how it regulates disease pathologies will pave the way for future development of therapeutic and preventive modalities for various human diseases.

Keywords:  cancer; cardiovasclar disease; infection; inflammation; inosine; neuroprotection

DOI:  https://doi.org/10.3389/fphar.2022.1043970
Pediatr Neonatol. 2022 Oct 26. pii: S1875-9572(22)00225-X. [Epub ahead of print]

Current and new therapies for mucopolysaccharidoses.

Monica Penon-Portmann, David R Blair, Paul Harmatz.

  The mucopolysaccharidoses (MPSs) are a subset of lysosomal storage diseases caused by deficiencies in the enzymes required to metabolize glycosaminoglycans (GAGs), a group of extracellular heteropolysaccharides that play diverse roles in human physiology. As a result, GAGs accumulate in multiple tissues, and affected patients typically develop progressive, multi-systemic symptoms in early childhood. Over the last 30 years, the treatments available for the MPSs have evolved tremendously. There are now multiple therapies that delay the progression of these debilitating disorders, although their effectiveness varies according to MPS sub-type. In this review, we discuss the basic principle underlying MPS treatment (enzymatic "cross correction"), and we review the three general modalities currently available: hematopoietic stem cell transplantation, enzymatic replacement, and gene therapy. For each treatment type, we discuss its effectiveness across the MPS subtypes, its inherent risks, and future directions. Long term, we suspect that treatment for the MPSs will continue to evolve, and through a combination of early diagnosis and effective management, these patients will continue to live longer lives with improved outcomes for quality of life.

Keywords:  enzyme replacement therapy (ERT); gene therapy (GT); hematopoietic stem cell transplantation (HSCT); lysosomal storage disease; mucopolysaccharidoses (MPS)

DOI:  https://doi.org/10.1016/j.pedneo.2022.10.001
Cancer Cell Int. 2022 Dec 09. 22(1): 395

Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis.

Cristina Quereda, Àngels Pastor, José Martín-Nieto.

  Dystroglycan (DG) is a glycoprotein composed of two subunits that remain non-covalently bound at the plasma membrane: α-DG, which is extracellular and heavily O-mannosyl glycosylated, and β-DG, an integral transmembrane polypeptide. α-DG is involved in the maintenance of tissue integrity and function in the adult, providing an O-glycosylation-dependent link for cells to their extracellular matrix. β-DG in turn contacts the cytoskeleton via dystrophin and participates in a variety of pathways transmitting extracellular signals to the nucleus. Increasing evidence exists of a pivotal role of DG in the modulation of normal cellular proliferation. In this context, deficiencies in DG glycosylation levels, in particular those affecting the so-called matriglycan structure, have been found in an ample variety of human tumors and cancer-derived cell lines. This occurs together with an underexpression of the DAG1 mRNA and/or its α-DG (core) polypeptide product or, more frequently, with a downregulation of β-DG protein levels. These changes are in general accompanied in tumor cells by a low expression of genes involved in the last steps of the α-DG O-mannosyl glycosylation pathway, namely POMT1/2, POMGNT2, CRPPA, B4GAT1 and LARGE1/2. On the other hand, a series of other genes acting earlier in this pathway are overexpressed in tumor cells, namely DOLK, DPM1/2/3, POMGNT1, B3GALNT2, POMK and FKTN, hence exerting instead a pro-oncogenic role. Finally, downregulation of β-DG, altered β-DG processing and/or impaired β-DG nuclear levels are increasingly found in human tumors and cell lines. It follows that DG itself, particular genes/proteins involved in its glycosylation and/or their interactors in the cell could be useful as biomarkers of certain types of human cancer, and/or as molecular targets of new therapies addressing these neoplasms.

Keywords:  Cancer; Dystroglycan; Gene expression; Glycosylation; Signal transduction; Tumorigenesis

DOI:  https://doi.org/10.1186/s12935-022-02812-7
Front Oncol. 2022 ;12 1070514

Glutamine metabolism and radiosensitivity: Beyond the Warburg effect.

Ryan S Alden, Mohammad Zahid Kamran, Bassel A Bashjawish, Brittany A Simone.

  Mounting data suggest that cancer cell metabolism can be utilized therapeutically to halt cell proliferation, metastasis and disease progression. Radiation therapy is a critical component of cancer treatment in curative and palliative settings. The use of metabolism-based therapeutics has become increasingly popular in combination with radiotherapy to overcome radioresistance. Over the past year, a focus on glutamine metabolism in the setting of cancer therapy has emerged. In this mini-review, we discuss several important ways (DNA damage repair, oxidative stress, epigenetic modification and immune modulation) glutamine metabolism drives cancer growth and progression, and present data that inhibition of glutamine utilization can lead to radiosensitization in preclinical models. Future research is needed in the clinical realm to determine whether glutamine antagonism is a feasible synergistic therapy that can be combined with radiotherapy.

Keywords:  cancer; glutamine (Gln); immunotherapy; metabolism; radiation; radiosensitivity; sirpiglenastat; telaglenastat

DOI:  https://doi.org/10.3389/fonc.2022.1070514
J Control Release. 2022 Dec 06. pii: S0168-3659(22)00817-3. [Epub ahead of print]

Targeting glycolysis for cancer therapy using drug delivery systems.

Yongzhuo Huang.

  There is close crosstalk between cancer metabolism and immunity. Cancer metabolism regulation is a promising therapeutic target for cancer immunotherapy. Warburg effect is characterized by abnormal glucose metabolism that includes common features of increased glucose uptake and lactate production. The aerobic glycolysis can reprogram the cancer cells and promote the formation of a suppressive immune microenvironment. As a case in point, lactate plays an essential role in tumorigenesis, which is the end product of glycolysis as well as serves as a fuel supporting cancer cell survival. Meanwhile, it is also an important immune regulator that drives immunosuppression in tumors. Immunometabolic therapy is to intervene tumor metabolism and regulate the related metabolites that participate in the innate and acquired immunity, thereby reinstalling the immune balance and eliciting anticancer immune responses. In this contribution to the Orations - New Horizons of the Journal of controlled Release I will provide an overview of glucose metabolism in tumors and its effects on drug resistance and tumor metastasis, and present the advance of glycolysis-targeting therapy strategies with drug delivery techniques, as well as discuss the challenges in glycolysis-targeting immunometabolic therapy.

Keywords:  Glycolysis; Immunotherapy; Nanomedicine; Targeted drug delivery; Tumor microenvironment; cancer metabolism

DOI:  https://doi.org/10.1016/j.jconrel.2022.12.003
Front Oncol. 2022 ;12 1055589

Hallmarks of cancer: The insulin-like growth factors perspective.

Haim Werner, Derek LeRoith.

  The identification of a series of attributes or hallmarks that are shared by virtually all cancer cells constitutes a true milestone in cancer research. The conceptualization of a catalogue of common genetic, molecular, biochemical and cellular events under a unifying Hallmarks of Cancer idea had a major impact in oncology. Furthermore, the fact that different types of cancer, ranging from pediatric tumors and leukemias to adult epithelial cancers, share a large number of fundamental traits reflects the universal nature of the biological events involved in oncogenesis. The dissection of a complex disease like cancer into a finite directory of hallmarks is of major basic and translational relevance. The role of insulin-like growth factor-1 (IGF1) as a progression/survival factor required for normal cell cycle transition has been firmly established. Similarly well characterized are the biochemical and cellular activities of IGF1 and IGF2 in the chain of events leading from a phenotypically normal cell to a diseased one harboring neoplastic traits, including growth factor independence, loss of cell-cell contact inhibition, chromosomal abnormalities, accumulation of mutations, activation of oncogenes, etc. The purpose of the present review is to provide an in-depth evaluation of the biology of IGF1 at the light of paradigms that emerge from analysis of cancer hallmarks. Given the fact that the IGF1 axis emerged in recent years as a promising therapeutic target, we believe that a careful exploration of this signaling system might be of critical importance on our ability to design and optimize cancer therapies.

Keywords:  IGF1 receptor (IGF1R); apoptosis; cancer hallmarks; cell cycle; insulin-like growth factor-1 (IGF1); p53; tumor suppressors

DOI:  https://doi.org/10.3389/fonc.2022.1055589
Chem Phys Lipids. 2022 Nov 30. pii: S0009-3084(22)00097-4. [Epub ahead of print]250 105269

Fatty acid transport proteins (FATPs) in cancer.

Ranjitha Acharya, Shilpa S Shetty, Suchetha Kumari N.

  Lipids play pivotal roles in cancer biology. Lipids have a wide range of biological roles, especially in cell membrane synthesis, serve as energetic molecules in regulating energy-demanding processes; and they play a significant role as signalling molecules and modulators of numerous cellular functions. Lipids may participate in the development of cancer through the fatty acid signalling pathway. Lipids consumed in the diet act as a key source of extracellular pools of fatty acids transported into the cellular system. Increased availability of lipids to cancer cells is due to increased uptake of fatty acids from adipose tissues. Lipids serve as a source of energy for rapidly dividing cancerous cells. Surviving requires the swift synthesis of biomass and membrane matrix to perform exclusive functions such as cell proliferation, growth, invasion, and angiogenesis. FATPs (fatty acid transport proteins) are a group of proteins involved in fatty acid uptake, mainly localized within cells and the cellular membrane, and have a key role in long-chain fatty acid transport. FATPs are composed of six isoforms that are tissue-specific and encoded by a specific gene. Previous studies have reported that FATPs can alter fatty acid metabolism, cell growth, and cell proliferation and are involved in the development of various cancers. They have shown increased expression in most cancers, such as melanoma, breast cancer, prostate cancer, renal cell carcinoma, hepatocellular carcinoma, bladder cancer, and lung cancer. This review introduces a variety of FATP isoforms and summarises their functions and their possible roles in the development of cancer.

Keywords:  Cancer; Fatty acid; Fatty acid transport proteins; Long-chain fatty acid; Solute carrier family 27 members (SLC27A)

DOI:  https://doi.org/10.1016/j.chemphyslip.2022.105269
Biochem Soc Trans. 2022 Dec 09. pii: BST20220735. [Epub ahead of print]

Functional regulation of Wnt protein through post-translational modifications.

Jia Yu, David M Virshup.

  Wnts are lipid-modified signaling glycoproteins present in all metazoans that play key roles in development and homeostasis. Post-translational modifications of Wnts regulate their function. Wnts have a unique post-translational modification, O-linked palmitoleation, that is absolutely required for their function. This Wnt-specific modification occurs during Wnt biosynthesis in the endoplasmic reticulum (ER), catalyzed by the O-acyltransferase Porcupine (PORCN). Palmitoleation is required for Wnt to bind to its transporter Wntless (WLS/Evi) as well as to its receptor Frizzled (FZD). Recent structural studies have illustrated how PORCN recognizes its substrates, and how drugs inhibit this. The abundance of WLS is tightly regulated by intracellular recycling and ubiquitylation-mediated degradation in the ER. The function of Wnt glycosylation is less well understood, and the sites and types of glycosylation are not largely conserved among different Wnts. In polarized tissues, the type of glycans can determine whether the route of trafficking is apical or basolateral. In addition, pairing of the 24 highly conserved cysteines in Wnts to form disulfide bonds is critical in maintaining proper structure and activities. Extracellularly, the amino terminus of a subset of Wnts can be cleaved by a dedicated glycosylphosphatidylinositol (GPI)-anchored metalloprotease TIKI, resulting in the inactivation of these Wnt proteins. Additionally, NOTUM is a secreted extracellular carboxylesterase that removes the palmitoleate moiety from Wnt, antagonizing its activity. In summary, Wnt signaling activity is controlled at multiple layers by post-translational modifications.

Keywords:  NOTUM; PORCN; TIKI; WLS; Wnt secretion; Wnt signaling

DOI:  https://doi.org/10.1042/BST20220735
Mol Pharm. 2022 Dec 08.

Phosphatidylserine in Diabetes Research.

Dandan Xiao, Wenguang Chang.

  Phospholipids are lipids that constitute the basic structure of cell membranes. In-depth research has shown that in addition to supporting cell structures, phospholipids participate in multiple cellular processes, including promoting cell signal transduction, guiding protein translocation, activating enzymatic activity, and eliminating dysfunctional/redundant organelles/cells. Diabetes is a chronic metabolic disease with a complicated etiology and pathology. Studies have shown that the level of certain phospholipids, for example, the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) in liver tissue, is negatively associated with insulin sensitivity. In addition, PS is a phospholipid exhibiting extensive cellular functions in diabetes. For this review, we analyzed many PS studies focusing on diabetes and insulin sensitivity in recent years and found that PS participates in controlling insulin secretion, regulating insulin signaling transduction, and participating in the progression of diabetic complications by mediating coagulation disorders in the microvasculature or targeting mitochondria. Moreover, PS supplements in food and PS-containing liposomes have been shown to protect against type 1 and type 2 diabetes (T1D and T2D, respectively) in animal studies. Therefore, by summarizing the regulatory roles played by PS in diabetes and the potential of successfully using PS or PS-containing liposomes for diabetic therapy, we hope to provide new ideas for further research into the mechanisms of diabetes and for drug development for treating diabetes and its complications.

Keywords:  PS species; diabetes; insulin secretion; insulin signaling pathway; phosphatidylserine

DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00707
Front Pharmacol. 2022 ;13 999017

Autophagy: An important target for natural products in the treatment of bone metabolic diseases.

Zhichao Li, Dandan Li, Hui Su, Haipeng Xue, Guoqing Tan, Zhanwang Xu.

  Bone homeostasis depends on a precise dynamic balance between bone resorption and bone formation, involving a series of complex and highly regulated steps. Any imbalance in this process can cause disturbances in bone metabolism and lead to the development of many associated bone diseases. Autophagy, one of the fundamental pathways for the degradation and recycling of proteins and organelles, is a fundamental process that regulates cellular and organismal homeostasis. Importantly, basic levels of autophagy are present in all types of bone-associated cells. Due to the cyclic nature of autophagy and the ongoing bone metabolism processes, autophagy is considered a new participant in bone maintenance. Novel therapeutic targets have emerged as a result of new mechanisms, and bone metabolism can be controlled by interfering with autophagy by focusing on certain regulatory molecules in autophagy. In parallel, several studies have reported that various natural products exhibit a good potential to mediate autophagy for the treatment of metabolic bone diseases. Therefore, we briefly described the process of autophagy, emphasizing its function in different cell types involved in bone development and metabolism (including bone marrow mesenchymal stem cells, osteoblasts, osteocytes, chondrocytes, and osteoclasts), and also summarized research advances in natural product-mediated autophagy for the treatment of metabolic bone disease caused by dysfunction of these cells (including osteoporosis, rheumatoid joints, osteoarthritis, fracture nonunion/delayed union). The objective of the study was to identify the function that autophagy serves in metabolic bone disease and the effects, potential, and challenges of natural products for the treatment of these diseases by targeting autophagy.

Keywords:  autophagy; bone metabolism; fracture nonunion/delayed union; natural products; osteoarthritis; osteoporosis; rheumatoid arthritis

DOI:  https://doi.org/10.3389/fphar.2022.999017
Curr Opin Chem Biol. 2022 Dec 06. pii: S1367-5931(22)00118-1. [Epub ahead of print]72 102233

Proximity labeling technologies to illuminate glycan-protein interactions.

Abigail E Reeves, Mia L Huang.

Glycosylation is a ubiquitous post-translational modification read by glycan-binding proteins (GBP) to encode important functions, but a robust understanding of these interactions and their consequences can be challenging to uncover. Glycan-GBP interactions are transient and weak, making them difficult to capture, and glycosylation is dynamic and heterogenous, necessitating study in native cellular environments to identify endogenous ligands. Proximity labeling, an experimental innovation that labels biomolecules close to a protein of interest, has recently emerged as a powerful strategy to overcome these limitations, allowing interactors to be tagged in cells for subsequent enrichment and identification by mass spectrometry-based proteomics. We will describe this nascent technique and discuss its applications in the last five years with different GBP classes, including Siglecs, galectins, and non-human lectins.

DOI: https://doi.org/10.1016/j.cbpa.2022.102233
Front Immunol. 2022 ;13 1063928

CNS and CNS diseases in relation to their immune system.

Jianhao Xu, Canyu Ma, Menglu Hua, Jiarui Li, Ze Xiang, Jian Wu.

  The central nervous system is the most important nervous system in vertebrates, which is responsible for transmitting information to the peripheral nervous system and controlling the body's activities. It mainly consists of the brain and spinal cord, which contains rich of neurons, the precision of the neural structures susceptible to damage from the outside world and from the internal factors of inflammation infection, leading to a series of central nervous system diseases, such as traumatic brain injury, nerve inflammation, etc., these diseases may cause irreversible damage on the central nervous or lead to subsequent chronic lesions. After disease or injury, the immune system of the central nervous system will play a role, releasing cytokines to recruit immune cells to enter, and the immune cells will differentiate according to the location and degree of the lesion, and become specific immune cells with different functions, recognize and phagocytose inflammatory factors, and repair the damaged neural structure. However, if the response of these immune cells is not suppressed, the overexpression of some genes can cause further damage to the central nervous system. There is a need to understand the molecular mechanisms by which these immune cells work, and this information may lead to immunotherapies that target certain diseases and avoid over-activation of immune cells. In this review, we summarized several immune cells that mainly play a role in the central nervous system and their roles, and also explained the response process of the immune system in the process of some common neurological diseases, which may provide new insights into the central nervous system.

Keywords:  central nervous system (CNS) injury; immune system; immunocytes; neuro-immune interaction; role

DOI:  https://doi.org/10.3389/fimmu.2022.1063928
Nat Rev Immunol. 2022 Dec 08.

CRISPR screens for functional interrogation of immunity.

Hao Shi, John G Doench, Hongbo Chi.

CRISPR-based technologies represent a major breakthrough in biomedical science as they offer a powerful platform for unbiased screening and functional genomics in various fields, including immunology. Pooled and arrayed CRISPR screens have uncovered previously unknown intracellular drivers in innate and adaptive immune cells for immune regulation as well as intercellular regulators mediating cell-cell interactions. Recent single-cell CRISPR screening platforms expand the readouts to the transcriptome and enable the inference of gene regulatory networks for better mechanistic insights. CRISPR screens also allow for mapping of genetic interactions to identify genes that synergize or alleviate complex immune phenotypes. Here, we review the progress in and emerging adaptation of CRISPR technologies to advance our fundamental immunological knowledge and identify novel disease targets for immunotherapy of infection, inflammation and cancer.

DOI: https://doi.org/10.1038/s41577-022-00802-4
Clin Exp Med. 2022 Dec 06.

Targeting redox regulation and autophagy systems in cancer stem cells.

Sameer Ullah Khan, Sheikh Rayees, Pankaj Sharma, Fayaz Malik.

  Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).

Keywords:  Autophagy; Cancer therapy; Mitophagy; Oxidative stress; Reactive oxygen species; Redox regulation; Redox-active compounds; Warburg effect

DOI:  https://doi.org/10.1007/s10238-022-00955-5
Kidney Dis (Basel). 2022 Nov;8(5): 368-380

The Growth Factors: Potential Biomarkers and Therapeutic Targets in Kidney Diseases.

Wei Tang, Yufeng Zhang, Sijia Cui, Fan Yi.

   Background: Kidney diseases are a prevalent health problem worldwide. Although substantial progress has been made in understanding the pathophysiology of kidney disease, currently there is no satisfactory clinical treatment available to prevent or treat kidney disease. Therefore, strategies to establish early diagnosis, identify the key molecules, and develop novel therapeutic interventions to slow the progression of kidney diseases and reduce their complications are encouraged.
Summary: The growth factors play a crucial role in the development of kidney diseases. The altered levels of growth factors are usually detected in circulation and urine in the disease course. A growing body of studies has suggested that growth factors, receptors, and related regulators are promising biomarkers for the diagnosis and/or prognosis and potential therapeutic targets for the treatment of kidney diseases. In this review, we summarize recent advances in the potential applications of growth factors for diagnostic biomarkers and therapeutic targets in kidney diseases and highlight their performances in clinical trials.
Key Messages: Most diagnostic and therapeutic strategies targeting growth factors are still far from clinical implementation. The better understanding of growth factor-regulated pathophysiology and the progress of new intervention approaches are expected to facilitate the clinical translation of growth factor-based diagnosis and therapy of kidney diseases.

Keywords:  Acute kidney injury; Chronic kidney disease; Clinical trials; Growth factors

DOI:  https://doi.org/10.1159/000526208
Adv Carbohydr Chem Biochem. 2022 ;pii: S0065-2318(22)00007-5. [Epub ahead of print]82 35-77

Pseudo-glycoconjugates with a C-glycoside linkage.

Go Hirai.

  Work by the author and colleagues has been focused on the development of pseudo-glycans (pseudo-glycoconjugates), in which the O-glycosidic linkage of the natural-type glycan structure is replaced by a C-glycosidic linkage. These analogs are not degraded by cellular glycoside hydrolases and are thus expected to be useful molecular tools that may maintain the original biological activity for a long period in the cell. However, their biological potential is not yet well understood because only a few pseudo glycans have so far been synthesized. This article aims to provide a bird's-eye view of our recent studies on the creation of C-glycoside analogs of ganglioside GM3 based on the CHF-sialoside linkage, and summarizes the chemical insights acquired during our stereoselective synthesis of the C-sialoside bond, ultimately leading to pseudo-GM3. Conformational analysis of the synthesized CHF-sialoside disaccharides confirmed that the anticipated conformational control by F-atom introduction was successful, and furthermore, enhanced the biological activity. In order to improve access to C-glycoside analogs based on pseudo-GM3, it is still important to streamline the synthesis process. With this in mind, we designed and developed a direct C-glycosylation method using atom-transfer radical coupling, and employed it in syntheses of pseudo-isomaltose and pseudo-KRN7000.

Keywords:  Anomeric radicals; C-glycoside analogs; Conformational analysis; Coupling reaction; Fluorine-containing C-glycosides; Kinetic pathway; Organic synthesis

DOI:  https://doi.org/10.1016/bs.accb.2022.10.002
Front Immunol. 2022 ;13 1063303

Multiplexed engineering and precision gene editing in cellular immunotherapy.

Alexander Biederstädt, Gohar Shahwar Manzar, May Daher.

  The advent of cellular immunotherapy in the clinic has entirely redrawn the treatment landscape for a growing number of human cancers. Genetically reprogrammed immune cells, including chimeric antigen receptor (CAR)-modified immune effector cells as well as T cell receptor (TCR) therapy, have demonstrated remarkable responses across different hard-to-treat patient populations. While these novel treatment options have had tremendous success in providing long-term remissions for a considerable fraction of treated patients, a number of challenges remain. Limited in vivo persistence and functional exhaustion of infused immune cells as well as tumor immune escape and on-target off-tumor toxicities are just some examples of the challenges which restrain the potency of today's genetically engineered cell products. Multiple engineering strategies are being explored to tackle these challenges.The advent of multiplexed precision genome editing has in recent years provided a flexible and highly modular toolkit to specifically address some of these challenges by targeted genetic interventions. This class of next-generation cellular therapeutics aims to endow engineered immune cells with enhanced functionality and shield them from immunosuppressive cues arising from intrinsic immune checkpoints as well as the hostile tumor microenvironment (TME). Previous efforts to introduce additional genetic modifications into immune cells have in large parts focused on nuclease-based tools like the CRISPR/Cas9 system or TALEN. However, nuclease-inactive platforms including base and prime editors have recently emerged and promise a potentially safer route to rewriting genetic sequences and introducing large segments of transgenic DNA without inducing double-strand breaks (DSBs). In this review, we discuss how these two exciting and emerging fields-cellular immunotherapy and precision genome editing-have co-evolved to enable a dramatic expansion in the possibilities to engineer personalized anti-cancer treatments. We will lay out how various engineering strategies in addition to nuclease-dependent and nuclease-inactive precision genome editing toolkits are increasingly being applied to overcome today's limitations to build more potent cellular therapeutics. We will reflect on how novel information-rich unbiased discovery approaches are continuously deepening our understanding of fundamental mechanisms governing tumor biology. We will conclude with a perspective of how multiplexed-engineered and gene edited cell products may upend today's treatment paradigms as they evolve into the next generation of more potent cellular immunotherapies.

Keywords:  CAR (chimeric antigen receptor); CRISPR screening; cell engineering; cell therapy; gene editing; immune effector cell

DOI:  https://doi.org/10.3389/fimmu.2022.1063303
Neuropsychiatr Dis Treat. 2022 ;18 2813-2835

Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage.

Bridget E Collins, Jeffrey L Neul.

  Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 (MECP2), which encodes the MeCP2 protein. RTT is a MECP2-related disorder, along with MECP2 duplication syndrome (MDS), caused by gain-of-function duplications of MECP2. Nearly two decades of research have advanced our knowledge of MeCP2 function in health and disease. The following review will discuss MeCP2 protein function and its dysregulation in the MECP2-related disorders RTT and MDS. This will include a discussion of the genetic underpinnings of these disorders, specifically how sporadic X-chromosome mutations arise and manifest in specific populations. We will then review current diagnostic guidelines and clinical manifestations of RTT and MDS. Next, we will delve into MeCP2 biology, describing the dual landscapes of methylated DNA and its reader MeCP2 across the neuronal genome as well as the function of MeCP2 as a transcriptional modulator. Following this, we will outline common MECP2 mutations and genotype-phenotype correlations in both diseases, with particular focus on mutations associated with relatively mild disease in RTT. We will also summarize decades of disease modeling and resulting molecular, synaptic, and behavioral phenotypes associated with RTT and MDS. Finally, we list several therapeutics in the development pipeline for RTT and MDS and available evidence of their safety and efficacy.

Keywords:  DNA methylation; disease modeling; epigenetics; neurodevelopmental disorders; therapeutics

DOI:  https://doi.org/10.2147/NDT.S371483
J Adv Res. 2022 Dec 05. pii: S2090-1232(22)00264-8. [Epub ahead of print]

Extracellular matrix in Skin Diseases: the road to new therapies.

M D Malta, M T Cerqueira, A P Marques.

   BACKGROUND: The extracellular matrix (ECM) is a vital structure with a dynamic and complex organization that plays an essential role in tissue homeostasis. In the skin, the ECM is arranged into two types of compartments: interstitial dermal matrix and basement membrane (BM). All evidence in the literature supports the notion that direct dysregulation of the composition, abundance or structure of one of these types of ECM, or indirect modifications in proteins that interact with them is linked to a wide range of human skin pathologies, including hereditary, autoimmune, and neoplastic diseases. Even though the ECM's key role in these pathologies has been widely documented, its potential as a therapeutic target has been overlooked.
AIM: of review:This review discusses the molecular mechanisms involved in three groups of skin ECM-related diseases - genetic, autoimmune, and neoplastic - and the recent therapeutic progress and opportunities targeting ECM. Key scientific concepts of review This article describes the implications of alterations in ECM components and in BM-associated molecules that are determinant for guaranteeing its function in different skin disorders. Also, ongoing clinical trials on ECM-targeted therapies are discussed together with future opportunities that may open new avenues for treating ECM-associated skin diseases.

Keywords:  ECM therapies; Extracellular matrix; autoimmune diseases; cutaneous cancer; genetic disorders

DOI:  https://doi.org/10.1016/j.jare.2022.11.008