LEAFY COTYLEDON (LEC) transcription factors, first discovered in Arabidopsis thaliana several decades ago, play a key role in regulating plant embryonic development, seed maturation, and subsequent growth. Existing studies have demonstrated that LECs together with other transcription factors form a huge and complex regulatory network to regulate many aspects of plant growth and development and respond to environmental stresses. Here, we focus on the role that has received little attention about the LECs linking different developmental stages and generational cycles in plants. We summarize the current fragmented research progress on the LECs role and molecular mechanism in connecting embryonic and vegetative growth periods and the reproductive stage. Furthermore, the possibility of LECs controlling the maintenance and transition of plant growth stages through epigenetic modifications is discussed.The life of higher plants progresses successively through embryonic, juvenile, adult, and reproductive stages.  The plant lifecycle goes through embryonic, juvenile, adult, and reproductive stages. Transitions between different developmental stages of plants ensure that plants can complete the lifecycle and maintain normal growth and development and adaptation to environmental stresses.LAFL that regulate embryonic development, including LEAFY COTYLEDON1 (LEC1) and LEC1-LIKE (L1L) of the NF-YB gene family, and ABSCISIC ACID INSENSITIVE3 (ABI3), FUSCA3 (FUS3), and LEC2 (LEAFY COTYLEDON2) of the B3-AFL gene family  are the key genes in plant embryonic development. During embryonic morphogenesis, the LEAFY COTYLEDONs (LECs) determine the fate of stalk cells and control cotyledon characteristics. In the later stage of embryonic maturation, ABI3 promotes the accumulation of storage substances and increases the dehydration resistance of embryos  family of transcription factors, which binds the CCAAT-box. The HAP complex includes three distinct subunits: HAP2/NF-YA/CBF-B, HAP3/NF-YB/CBF-A, and HAP5/NF-YC/CBF-C, and HAP3 plays an important role in plant embryonic development, chlorophyll biosynthesis, flowering regulation, etc.  cis-regulator. Numerous studies have shown that these genes are involved in embryonic development and need to be inhibited in the vegetative phase after seed germination to ensure that the plant can enter the vegetative phase smoothly  and elucidate the molecular and epigenetic mechanisms of embryonic developmental regulators that play a role in linking different developmental stages to regulate the plant life cycle. In addition, previous studies were mostly limited to the function of LEAFY COTYLEDONs at a specific developmental stage. Hence, little attention has been paid to the role of LEAFY COTYLEDONs in plant phase transition and life cycle, and there is a lack of systematic and in-depth research on its molecular mechanism. We further examine the molecular mechanisms by which LECs regulate plant phase transitions and propose a possible model of the complete life cycle.Here, we focus on LEAFY COTYLEDONs  that are activated in sequence . Dicotyledonous embryogenesis starts from the fertilized egg (zygote), which is divided into several morphologically distinct stages: proembryo, heart-shaped embryo, spherical embryo, torpedo-shaped embryo, and horseshoe-shaped embryo . After esequence .FUS3/LEC type genes to enable the seed to enter the maturity stage, as mutations in these genes cause a continuation of growth of immature embryos  gene family  1 and 2 are required for establishing and maintaining stable epigenetic repression in response to developmental or environmental signals  activity, and PRC1 can recognize H3K27me3 and lead to chromatin compaction through histone H2A lysine ubiquitination  are transcriptional regulators containing DNA-and chromatin-binding domains, and the expression of VAL1 and 2 increased in this process as embryo-repressed genes  marks to initiate initial repression of the target gene  are also upregulated in the process, and they are members of the CHD3 family of chromatin ATPase remodelers  have a direct interdependent relationship, and can jointly bind to the promoter G-box elements of the hypocotyl elongation-related genes such as INDOLE-3-ACETIC ACID INDUCIBLE 19 (IAA19) and CYTOKININ INDUCED ROOT CURLING 2 (YUC8), and coordinately regulate hypocotyl elongation (LEC1 inhibited the development of cotyledon trichomes by regulating the expression of the trichome development-related genes such as GLABROUS1 (GL1), GL2, and GL3 and recruiting the transcription factor TRICHOMELESS2  have also been shown to be associated with root development. In culture medium free of any exogenous hormone supplementation, while adventitious root emergence and growth was prominently observed in wild-type cells, no such features were observed in abi3-6 cells  and synergistically activate its transcription during lateral root formation  in Arabidopsis, and exogenous application of JA delays VPC and rejuvenizes leaf five in both epidermal characteristics and gene expression patterns ; this pathway mechanism is evolutionary conserved . However, it remains unclear whether these two pathways cross and what their molecular mechanisms are.In addition, patterns . Using Gonserved . To sum Polycomb repressive group complex 2 (PRC2) inhibits gene expression by catalyzing the trimethylation of histone H3 at lysine 27  and SWINGER (SWN) binding regions through ChIP seq analyses to profile the genome-wide distributions of CLF and SWN in Arabidopsis seedlings  and other active chromatin modifiers  is a SWI2/SNF2 chromatin remodeling ATPase, and BRM antagonizes the PcG protein complexed with SWN protein influencing the histone methylation status of the MIR156A promoter region , as a negative regulator of seed germination, needs to be suppressed before seedling development. This repressive signal is mediated by PRC1 and PRC2, as well as PKL and PICKLERELATED2 (PKR2) proteins  proteins EMF1, CLF, LHP, and SWN are involved in these processes. FUSCA3 has been shown to perform different functions in embryonic and vegetative stages, synergize with JA, GA, and ABA, and participate in the epigenetic modification process to regulate the stage transition in plants. LEAFY COTYLEDONs form a complex network with histone epigenetic modifiers, miRNAs, and transcription factors specifically expressed at each growth stage, and they also mediate phytohormone signals. However, previous studies were mostly limited to the function of LEAFY COTYLEDONs at a specific developmental stage, with little attention paid to the role of LEAFY COTYLEDONs in plant phase transition and life cycle. However, the progression of the life cycle is critical for perennials. During the cycle of each generation, the reactivation of many genes is required to start a new round of life activities. For example, the flowering suppressor gene FLC is reset by LEAFY COTYLEDONs during embryonic stage, and the age master gene miR156A/C is reset by LEAFY COTYLEDONs during embryonic stage. A growing number of studies have demonstrated the critical role of LEC genes in altering plant generations, but these studies are only in their infancy. We hope this paper will provide new research ideas for researchers to study various physiological activities associated with the alteration of plant generations. LEAFY COTYLEDONs are involved in many physiological and biochemical processes in plants, especially in epigenetic modifications, which we believe play a crucial role in tandem with different developmental stages in plants. We propose a model for the role of LEAFY COTYLEDONs in linking different growth stages and completing the generational cycle in this study (LEAFY COTYLEDONs’ intrinsic molecular mechanism has far-reaching significance for understanding the principle of the plant lifecycle and applying it to agricultural production.The development of higher plants starts from the zygote, and plants already begin to prepare for subsequent vegetative growth, flowering, and reproduction during embryonic development. However, there are many studies on the relationship between vegetative growth and reproductive growth, but few studies on how the embryonic stage affects vegetative growth and reproductive growth. In fact, epigenetic modification in the embryonic stage allows the plant to remember this modification and pass it on to the postembryonic vegetative and reproductive growth stages. We think that is study . FurtherCC and XD contributed to the conception and design of the study. CC wrote the first draft of the manuscript. XD make critical revisions to the work. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The sorting nexin (SNX) family of proteins mediate the sorting and trafficking of endocytosed transmembrane proteins between the endosomal compartments, lysosome, trans-Golgi network, and plasma membrane. SNXs are characterized by the presence of a Phox domain; however, SNX27 is a unique member of this family as it contains an additional PDZ domain. Evidence suggests that SNX27, in association with the retromer complex, binds cargo via its PDZ domain and recycles them from the early endosomes to the plasma membrane, thereby escaping their lysosomal degradation. The roles of SNX27 in cancer is largely unexplored, however many of its identified cargoes have been indicated in tumorigenesis. In this review we provide a summary of the current knowledge, as supported by scientific literature and evidence, regarding the fundamental structure, biological function, and implication of SNX27 in human cancers.SNX27 belongs to the sorting nexin (SNX) family of proteins that play a critical role in protein sorting and trafficking in the endocytosis pathway. This protein family is characterized by the presence of a Phox (PX) domain; however, SNX27 is unique in containing an additional PDZ domain. Recently, SNX27 has gained popularity as an important sorting protein that is associated with the retromer complex and mediates the recycling of internalized proteins from endosomes to the plasma membrane in a PDZ domain-dependent manner. Over 100 cell surface proteins have been identified as binding partners of the SNX27–retromer complex. However, the roles and underlying mechanisms governed by SNX27 in tumorigenesis remains to be poorly understood. Many of its known binding partners include several G-protein coupled receptors, such as β2-andrenergic receptor and parathyroid hormone receptor, are associated with multiple pathways implicated in oncogenic signaling and tumorigenesis. Additionally, SNX27 mediates the recycling of GLUT1 and the activation of mTORC1, both of which can regulate intracellular energy balance and promote cell survival and proliferation under conditions of nutrient deprivation. In this review, we summarize the structure and fundamental roles of SNX proteins, with a focus on SNX27, and provide the current evidence indicating towards the role of SNX27 in human cancers. We also discuss the gap in the field and future direction of SNX27 research. Insights into the emerging roles and mechanism of SNX27 in cancers will provide better development strategies to prevent and treat tumorigenesis.  SNX27 belongs to the large family of SNX proteins whose fundamental role involves the regulation of intracellular trafficking, as well as sorting of internalized cargo through the complicated cascade of the endocytic pathway . The SNXEndocytosis is a crucial cellular process that internalizes cargoes from the cell surface and transports them in membrane-bound vesicles for sorting into either of its two destined fates: lysosomal degradation or recycling back to the plasma membrane . ImpropeRetromer is an endosomal coat protein complex first identified in the endolysosomal system of budding yeast . It is eInteractions between the intracellular compartments and the extracellular environment need to be closely monitored in order to maintain cellular homeostasis . TherefoEmerging evidence suggests a potential role of SNXs in human cancers, although the research is still limited. This review is aimed towards summarizing scientific evidence supporting and providing an update on the current molecular understanding of SNX27, its associations with the sorting and transport of internalized endosomal cargo, and its implication in cancers.Since the discovery of the first sorting nexin, a total of 10 family members have been identified in yeast and 33 members in mammals . TypicalOne of the most critical physiological roles of SNX proteins that has been studied so far is their ability to mediate the trafficking of endocytosed cargoes from the compartments of early endosomes to either the TGN or the plasma membrane . HoweverSNX3 belongs to the SNX-PX subfamily of SNX proteins as it contains only the PX domain. The association of SNX3 with the retromer subunit, VPS26, has been shown to be crucial for cargo recognition, binding, and retrograde recycling to the TGN . This isIn mammals, up to twelve members of the SNX-BAR subfamily have been identified which possess a Bin/Amphiphysin/Rvs (BAR) domain in addition to the highly conserved PX domain . Among tSNX27 was identified as another retromer associated SNX protein belonging to the SNX-FERM subfamily. Members of this subfamily contain a PX domain and a C-terminal 4.1/ezrin/radixin/moesin (FERM) domain . The mecIn addition to their primary role in endocytic recycling, some SNX proteins are involved in the process of endocytosis and lysosomal degradation. SNX9 and SNX18 carry an N-terminal SH3 domain in addition to the C-terminal BAR domain . While SAs shown in SNX27 was initially discovered in the brain tissue where it was found to be interacting with 5-HT4.a/R, a G-protein coupled receptor (GPCR) . StructuEndocytosed transmembrane proteins require to go through a complex network of the endomembrane system that is subdivided into the early, late, and recycling endosome vesicles. While the cargo sorted in late endosomes proceed for lysosomal degradation, those present in the recycling endosomes further interact with the components of the secretory pathway in order to be transported to either the TGN or delivered back to the cell surface . TherefoSorting and recycling of the transmembrane proteins from early/recycling endosomal compartments directly to the plasma membrane is heavily dependent on the association of the SNX27/SNX-BAR/retromer complex on Rab4-positive endosomes . In thisWhile the PX domain drives SNX27 membrane recruitment, structure-based analyses have shown that the synergistic interaction of the FERM domain with the endosomal membranes also enhances localization of the SNX27-retromer complex to the endosomes, as disrupting the FERM domain decreased the affinity between SNX27 and the endosomal compartments . The actin remodeling WASH complex, which consists of the WASH1, WASHC3, WASHC4, WASHC5, and FAM21 subunits , was ideAmong the many identified PDZ-domain-containing cargoes dependent on the SNX27-retromer-mediated endosome-to-plasma membrane recycling see , β-2-andIn contrast to the canonical mechanism of class-1 PDZ-binding motifs necessary for interaction with SNX27, it was recently observed that MT1-MMP, which lacks a class-1 PDZ-binding motif on its C-terminus, is still able to bind to the SNX27-retromer complex and is recycled to the cell surface in a SNX27-retomer-dependent manner . StructuOverall, SNX27’s interacts with various transmembrane proteins for the maintenance of their cell surface levels and activity. It suggests that loss of SNX27 may lead to an array of cellular dysfunction, which has been reciprocated in vivo as SNX27 whole-body knockout mice have been shown to be embryonically lethal .https://www.proteinatlas.org/ENSG00000143376-SNX27/tissue, accessed on 21 December 2022). Primarily, SNX27 was studied in the brain–nervous system and related diseases. However, we believe its role in other organs could be equally critical.SNX27 is found to be expressed in almost every cell type, based on the data from Human Atlas  in a T-cell receptor (TCR) activation dependent manner . Cells oUnder unstimulated conditions, SNX27 is predominantly expressed on the PtdIns[1]P-rich membranes of early and recycling endosomes, which then rapidly polarizes towards the IS upon TCR activation . StructuProteomic analysis of the SNX27 interactome in IS forming activated T-cell lymphocytes has not only confirmed the participation of retromer and WASH complexes in SNX27-mediated polarized trafficking, but also revealed several SNX27 interacting cargoes that are presented at the IS in a PDZ-dependent manner, e.g., diacylglycerol kinase-ζ (DGKζ) ,72. TCR The identification of DGKζ and its association with SNX27 provides novel insights into DAG associated T-cell activation. It also suggests the tissue specific role of SNX27 in immune system. Further investigation is required to determine the extent of SNX27-mediated regulation of IS assembly and participation of other SNX27-interacting cargoes in this process. Underlying the importance of SNX27 mediated endocytic recycling of a wide array of transmembrane proteins with distinct functions, SNX27 is necessary for proper functioning of human health .The PDZ binding motif is most commonly found in proteins involved in excitatory synapses, and thus located within regions of postsynaptic densities in the neurons . In the Multiple studies have shown enlargement of early endosomes and multivesicular bodies in brain tissues and neurons isolated from human as well murine models of Alzheimer’s disease (AD), overall suggesting defects in endocytic trafficking and recycling pathways ,81. SNX2SNX27 has also been reported to contribute towards impairment in neuronal and learning abilities in Down’s Syndrome (DS) . The oveLastly, SNX27 has been shown to recycle AMPA and NMDA glutamate receptors ,78. GlutIncreasing evidence suggests that SNX27 may mediate cancer development and/or progression as it influences distinct protein–protein interactions, membrane remodeling, and cell surface expression of several important tight junction proteins and receptors implicated in cell signaling pathways see  35]. Hu. Hu35]. We have previously demonstrated that loss of SNX27 dramatically reduces tumor growth and proliferation in breast cancer cells, which was further confirmed via mouse xenograft models . We furtAnother study investigating the associations of SNX27 and breast cancer metastasis revealed that SNX27 directly interacts with MT1-MMP, a key enzyme recruited by invadopodia for degradation and remodeling of the extracellular matrix . The in Several studies have revealed protein candidates from the GPCR superfamily which interact with SNX27. These include the β2-andrenergic receptor , parathySNX27 is involved in cellular nutrient uptake as it directly interacts with and recycles GLUT1, facilitator of glucose transport across the plasma membrane, which promotes cell growth and survival . The mTOTaken together, SNX27 may potentially exhibit its roles and regulate different stages of tumorigenesis, as we proposed in the Graphic abstract. Observations from previous studies indicate a potential therapeutic strategy of targeting SNX27 for cancer treatment, however further research is required to fully elucidate the role of SNX27 in tumorigenesis.Owing to the canonical physiological roles of the SNX family of proteins in mediating the endocytic pathway and intracellular protein trafficking, several SNXs have been involved in crucial intracellular signaling cascades, such as the Notch, EGFR, and Wnt signaling pathways, to name a few . These pA study by Zhan et al. reported that the overall mRNA and protein expression levels of SNX1 was lower in gastric cancer patients, which also correlated with poor patient survival . As in vThe first report of SNX5 in human cancers was identified in thyroid cancer where the expression levels of SNX5 decreased through the progression of well-differentiated to poorly differentiated tumors , the latSNX6 has been reported in pancreatic cancer and implicated in regulating EMT and invasiveness of cancer cells . Loss ofA series of studies published by Bendris et al. revealed that SNX9 is differentially expressed through different stages of breast cancer, which can affect the functions of SNX9 as executed in different cancer cells. However, the exact mechanism regulating this phenomenon remains unclear . It was SNX10 deficiency promotes the initiation and progression of colorectal cancer in mice. Consistent to these observations, SNX10 expression levels were found to be much lower in human colorectal cancer tissues. Further analysis into the mechanism of SNX10 driven colorectal tumorigenesis revealed that loss of SNX10 activates chaperone-mediated autophagy (CMA) and increases the degradation of tumor suppressor p21 in a CMA dependent manner . This waAs we have described above the incidence and roles of SNX proteins in various solid tumors, in this section we will discuss the reports of SNX family members particularly in liquid cancers, such as lymphoma, leukemia, and myeloma  . This stAlthough direct validation studies have not been conducted yet, there are speculations that SNX9 may also play a role in the development of liquid cancers. A recent siRNA mediated knockdown study has reported that the loss of SNX9 dramatically reduces internalization of ADAM9 . PreviouSNX27, the most unique member of the SNX family, has also been identified to play a role in leukemia. An RNAi screen conducted in primary AML cells reported that SNX27 promotes AML tumorigenesis and may serve as a potential prognostic marker, since a lack of SNX27 dramatically reduces tumor cell growth and viability . More reA lot of research has been focused on unravelling the fundamental roles of SNXs in synchronizing the various stages of endosomal cargo selection and transport . The SNXSNX27 is the most unique member of the SNX family of proteins which mediates endocytic recycling of several critical transmembrane proteins in a PDZ-domain dependent manner . HoweverSeveral studies have implicated SNX27 in regulating various cancers, particularly breast cancer . This ha


Fibroblast growth factor 21 (FGF21), a member of fibroblast growth factor family, is a hormone-like growth factor that is synthesized mainly in the liver and adipose tissue. FGF21 regulates lipid and glucose metabolism and has substantial roles in decreasing lipogenesis and increasing hepatic insulin sensitivity which causing lipid profile improvement. FGF21 genetic variations also affect nutritional and addictive behaviors such as smoking and alcohol consumption and eating sweets. The role of FGF21 in metabolic associated diseases like diabetes mellitus had been confirmed previously. Recently, several studies have demonstrated a correlation between FGF21 and liver diseases. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease worldwide. NAFLD has a wide range from simple steatosis to steatohepatitis with or without fibrosis and cirrhosis. Elevated serum levels of FGF21 associated with NAFLD and its pathogenesis. Alcoholic fatty liver disease (AFLD), another condition that cause liver injury, significantly increased FGF21 levels as a protective factor; FGF21 can reverse the progression of AFLD and can be a potential therapeutic agent for it. Also, NAFLD and AFLD are the most important risk factors for hepatocellular carcinoma (HCC) which is the fourth deadliest cancer in the world. Several studies showed that lack of FGF21 induced oncogenic condition and worsened HCC. In this review article, we intend to discuss different aspects of FGF21 in NAFLD, AFLD and HCC; including the role of FGF21 in pathophysiology of these conditions, the effects of FGF21 mutations, the possible use of the FGF21 as a biomarker in different stages of these diseases, as well as the usage of FGF21 and its analog molecules in the treatment of these diseases. Fibroblast growth factor 21 (FGF21) is an endocrine regulating factor that is produced mainly in the liver and adipose tissues –5. It isThe liver is one of the most important organs in the body because of its crucial role in several processes including detoxification, anabolism and catabolism, immune factors production and lipids metabolism regulation. The liver's functions can be affected by several diseases. Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Insulin resistance, lipid metabolism dysfunctions and inflammation are the major causes of NAFLD . Decreasvia induction of inflammation and accumulation of lipids in the liver . About 50% of cirrhosis-related death is attributed to alcohol consumption . ChronicIn this review article, we attempt to concisely explain the role of FGF21 and its mutations and analogs on liver disorders. Further studies will be required to determine the effectiveness and accuracy of FGF21 and its analogs in targeted therapy to cure and diagnose hepatic disorders.FGF21 is a hormone-like growth factor composed of 209 amino acids . FGF21 pSeveral studies confirmed that FGF21 has an important role in lipid and carbohydrate metabolism as well as energy and nutrient homeostasis . Hence, FGF21 increases hepatic insulin sensitivity, decreases lipogenesis, triggers fatty acid β-oxidation, reduces hepatic ER stress, and diminishes VLDL delivery to the liver (through down-regulation of VLDL receptor expression in hepatocytes) –5. FGF21FGF21 levels are positively correlated with obesity, body mass index (BMI) and hepatic fat accumulation . It is dFGF21 level increased in T2DM and is positively correlated with hyperglycemia, insulin resistance and inflammatory processes , 4, 6. PIn contrast to mouse models, short-term fasting or ketogenic diets do not increase FGF21 levels in humans , 42. FGFFGF21 also is elevated in patients with atherosclerosis . SeveralThese findings suggested that FGF21 increased in obesity and other related conditions such as T2DM, metabolic syndrome, fatty liver disease, etc. FGF21 has several important roles in lipid and carbohydrate metabolism and energy homeostasis which it's important roles summarized in To the best of our knowledge, there are not enough studies about the association of genetic variations of FGF21 with hepatic diseases such as NAFLD, NASH, and HCC. While FGF21 can affect the pathomechanism of these diseases, it can also play an important role as a biomarker for NAFLD and AFLD and show significant results in curing fatty liver and metabolic associated diseases. In a study done on a Han Chinese non-diabetic population the association of four Single Nucleotide Polymorphisms (SNPs) with NAFLD was investigated . They fovia changes in folding and stability of FGF21 mRNA (Another study was done in order to discover the association between genetic variations of FGF21 and Metabolic Associated Fatty liver diseases (MAFLDs) suggesting that rs838136 could be a risk factor for MAFLDs F21 mRNA .via producing different hormones like FGF21  is a metabolic regulator which senses the oxidative stress and reduced energy charge of body. Several energy-generating pathways such as glycolysis and fatty acid oxidation are up-regulated by AMPK . AMPK alBesides, alcohol exposure may lead to hepatic fat accumulation, hepatic ER stress and inflammation which results in FGF21 production . SeveralAccording to these findings, FGF21 might be a potential target for AFLD treatment and further trials are required to investigate its effects as a therapeutic agent in humans.Non-alcoholic fatty liver disease is nowadays the most common chronic liver disease in the world. It affects 1.8 billion people worldwide with a prevalence of about 30% of the adult population , 76. NAFde-novo lipogenesis  and Hepatitis B Virus (HBV) can be major risk factors for HCC . FGF21 ivia activating of hepatocyte FGFR4, it accelerates the progression of tumors to HCC by interacting with FGFR1  and bodyweight.According to the important effects of FGF21 on metabolic associated diseases some clinical trials have been established in order to assess the safety and therapeutic efficacy of human FGF21 analogs and FGF21 receptor agonists . NeverthLY2405319, a glycosylated FGF21 variant, in a randomized, double-blind, placebo-controlled study demonstrated significant improvements in lipid profile, body weight and adiponectin level in obese and T2DM patients . The maiPF-05231023, another FGF21 long-acting analog, considerably reduced body weight, plasma TGs and LDLs and increased HDLs and adiponectin in overweight or obese subjects with T2DM , 34. HowA PEGylated FGF21 analog called Pegbelfermin (formerly BMS-986036) was tested in biopsy-confirmed NASH patients previously . This stEfruxifermin, a long-acting Fc-FGF21 fusion protein was assessed in a trial for the treatment of NASH . This stBFKB8488A is a humanized antibody that specifically activates the FGFR1/β-Klotho complex . In phasMK-3655, a monoclonal antibody targeted to β-klotho and FGFR1c, in a clinical trial in phase 2 showed improvements in glycemic control and reduction in liver fat content while decreasing serum TG and LDL , 105.LLF580, a genetically engineered variant of human FGF21, demonstrated beneficial effects on serum lipids profile  in obese and mildly hypertriglyceridemic adults . This stThese clinical trials on FGF21 analogs and mimetics showed that they could be used as potential therapeutic agents for metabolic and liver disorders. Besides, safety concerns for instance cardiovascular side effects and possibility of bone loss raise the questions like will FGF21 analogs be safe in chronic treatments and how would potential side effects including anti-drug antibodies  influencTherefore, larger and long-term trials should be established in order to assess their safety and efficacy.Taken together our review suggested that FGF21 has a major role in the pathophysiology and treatment of AFLD, NAFLD and HCC. Administrating of FGF21 analogs and mimetics has demonstrated therapeutic benefit in human and rodent models of metabolic diseases, but still more studies and clinical trials will be required to prove the efficacy of these treatments. FGF21 is also used as a diagnostic biomarker for metabolic associated diseases of the liver. Also, despite the few studies that have been done on the genetic variations of FGF21, significant results have been obtained regarding the direct and indirect effects of these variations on metabolic diseases. In summary, the present study suggests that FGF21 administration can ameliorate fatty liver diseases and HCC furthermore studies are needed.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Photodynamic therapy (PDT) was discovered more than 100 years ago. Since then, many protocols and agents for PDT have been proposed for the treatment of several types of cancer. Traditionally, cell death induced by PDT was categorized into three types: apoptosis, cell death associated with autophagy, and necrosis. However, with the discovery of several other regulated cell death modalities in recent years, it has become clear that this is a rather simple understanding of the mechanisms of action of PDT. New observations revealed that cancer cells exposed to PDT can pass through various non-conventional cell death pathways, such as paraptosis, parthanatos, mitotic catastrophe, pyroptosis, necroptosis, and ferroptosis. Nowadays, immunogenic cell death (ICD) has become one of the most promising ways to eradicate tumor cells by activation of the T-cell adaptive immune response and induction of long-term immunological memory. ICD can be triggered by many anti-cancer treatment methods, including PDT. In this review, we critically discuss recent findings on the non-conventional cell death mechanisms triggered by PDT. Next, we emphasize the role and contribution of ICD in these PDT-induced non-conventional cell death modalities. Finally, we discuss the obstacles and propose several areas of research that will help to overcome these challenges and lead to the development of highly effective anti-cancer therapy based on PDT. PDT is a widely used and useful tool in the treatment of multiple types of cancer, but its treatment modes still need to be adjusted to the needs of each patient according to the individual characteristics of a tumor.The efficacy of PDT depends largely on the activation of ICD that enables the immune system to engage in the combat against any remaining tumor cells and to generate long-lasting immunological memory.Many cell death modalities with immunogenic or non-immunogenic properties that can be induced by PDT have been recently discovered, and this list is still growing. They include mitotic catastrophe, paraptosis, pyroptosis, parthanatos, necroptosis and ferroptosis.To overcome tumor cell resistance to cell death, there is a need to induce different cell death types, including mixed cell death types, coupled with different combinations of PDT irradiation regimens and photosensitizers. This will provide novel and effective therapeutic strategies and will contribute to a so-called “ideal protocol” for PDT in cancer therapy.Which factors determine how to trigger of specific PDT-induced cancer cell death type?How can we overcome the resistance of cancer cells to certain types of death, and in particular apoptosis and necroptosis? Is the induction of mixed types of cell death a promising approach for overcoming such resistance?Is it worthwhile to induce ferroptosis by PDT during development of new approaches aimed at increasing the effectiveness of PDT against resistant and highly malignant tumors?An ideal protocol for PDT of cancer needs to be formulated.The discovery of the main principles of photodynamic reactions more than 100 years ago  gave a p1PS•) can undergo transformation into a long-lived excited triplet state (3PS•) via an intersystem crossing process that launches two kinds of photochemical reactions with adjacent molecules. In the type I photochemical reaction, 3PS• interacts directly with polyunsaturated fatty acids in cell membrane lipids, to which it transfers an electron or a proton to form organic radicals. Upon interaction with cellular oxygen, these radicals can generate cytotoxic reactive oxygen species (ROS), e.g., superoxide anion (O2–•), hydroperoxide radical (HOO•), peroxides  and hydroxyl radical (HO•), which launch free radical chain reactions. The type II photochemical reaction initiates triplet−triplet energy transfer of 3PS• to molecular oxygen, resulting in the formation of singlet oxygen (1O2), which serves as a powerful oxidizing agent. Type I and type II photochemical reactions can proceed simultaneously, and the ratio between them depends mainly on the photochemical and photophysical characteristics of the PS and the concentrations of substrate and cellular oxygen. Type I and type II photochemical reactions trigger different cell death mechanisms that are directly cytotoxic to cancer cells and lead to tumor tissue destruction , its accumulation in tumor cells, and subsequent excitation by irradiation with visible light of appropriate wavelength Fig. . The excconventional” cell death pathways of apoptosis, necrosis and autophagy  in patients with non-operable sarcomas in the 19th century , 19, bute system , a majorFollowing the principles of cancer immunotherapy, an ideal PDT protocol should successfully destroy the primary tumor while activating the immunogenic cell death pathway. This allows the activation of the immune system to identify and destroy residual tumor cells, including those in distant metastases. Notably, PDT can induce different immunogenic cell death modalities, e.g., apoptosis , necroptIn this review, we discuss non-conventional cell death modalities that can be induced by PDT. We focus on mitotic catastrophe, paraptosis, pyroptosis, parthanatos, necroptosis, and ferroptosis, and we assess their relevance in anticancer therapy. Next, we emphasize the role and contribution of ICD in these PDT-induced non-conventional cell death modalities. Finally, we discuss the prospects for developing strategies to enhance PDT efficacy in cancer treatment.Box 1 Anti-cancer PDT in the clinic: the current state and new trendsAfter a century, PDT has taken its rightful place among the powerful cancer treatment modalities , 202. PDSeveral groups of PSs have been clinically approved for anti-cancer PDT, with most of them containing porphyrin compounds as an active ingredient . These aAmong the most important advantages of PDT is low systemic toxicity because the cytotoxic effect of the PS in the absence of light irradiation is several orders of magnitude lower than in the irradiated cancer tissue. But a current limitation is the mode of light delivery, which is currently restricts treatment to superficial tumors or tumors accessible with an endoscope: non-melanoma skin cancer , retina Strictly speaking, artificial light sources are not required for PDT. The recently developed daylight PDT (dPDT) has become a powerful tool for treatment of skin cancer and precancerous lesions , 225. InPDT can be applied as a primary therapy in some clinical situations, but it has also proven to be a potent adjuvant anticancer treatment when combined with surgery, chemotherapy or radiotherapy. Since demonstration of the induction of ICD by PDT and its promotion of anticancer immune responses in the last decade , 226, inBox 2 Conventional and non-conventional cell death modalities in PDT – which is which?Over several decades, cell death induced by PDT was conventionally categorized into three types, the so-called “three classical pillars” of cell death: type I (apoptosis), type II (autophagy), and type III (necrosis) , 228. Whnon-conventional forms of cell death generated by PDT have different morphological, biochemical, genetic, and functional properties from the well-known “three pillars” of cell death. The guidelines for definition and interpretation of cell death approved by the Nomenclature Committee on Cell Death in 2018 describe more than 10 cell death modalities  phenyl-tetracyanoporphyrazine, induced a mixed types cell death (apoptosis and necroptosis) and triggered a pronounced immunogenic response in vitro  and demonstrated the protective effect against fibrosarcoma MCA205 cells in the tumor prophylactic vaccination model in immunocompetent C57BL/6 J mice . Notably2 nano-flowers [2 nanomaterial [In addition to the development of new effective strategies for anti-cancer therapy, an equally important issue is the timely diagnosis of the tumor. Recently, nano-theranostic agents intended for MRI-guided photothermal/PDT (PTT/PDT) have been developed. The advantage of this approach is simultaneous monitoring by MRI imaging and killing of tumors with high specificity and therapeutic efficiency by induction of PTT/PDT without causing systemic side effects , 146. Itmaterial . HoweverIn 2012, the research group of B. Stockwell discovered a new cell death modality selectively triggered by the oncogenic RAS-selective lethal small molecule, erastin. This cell death modality was named ferroptosis  provides a cystine supply and is responsible for maintaining a cellular antioxidant environment that prevents ROS production. GPX4 is a selenoprotein required for detoxifying lipid peroxides and decreasing the activity of phospholipid peroxidation inducers. Disrupting the system xc- or decreasing the levels of GPX4 leads to exhaustion of antioxidant cysteine–glutathione (GSH) metabolism. In this regard, lipid peroxides cannot be metabolized, and Fe2+ oxidizes lipids via the Fenton reaction, which leads to the production of highly toxic lipid peroxides and cell death [Ferroptosis is regulated by multiple genes primarily related to iron homeostasis and lipid peroxidation metabolism , which have been reviewed recently , 153. Holl death , 155. Thll death . Lipid pll death .2  [Ferroptosis inducers other than erastin are known, including the small molecule compound Ras Selective Lethal 3 (RSL3) (inactivates GPX4) , FIN56 (idation) , 159.The evidence so far indicates that ferroptosis may be involved in diverse biological processes in mammals as well as the emergence and further development of several pathological processes, such as ischemia‒reperfusion injury, renal failure, nervous system diseases, hematologic diseases, and tumorigenesis , 160. Fe−/− mice, suggesting that the mechanism of ferroptosis immunogenicity is very tightly regulated by the adaptive immune system and is dependent on the cell death stage [From the viewpoint of anticancer therapy, ferroptosis is considered as an alternative cell death mode for eradicating tumors resistant to apoptosis and/or necroptosis. It is noteworthy that the process of ferroptosis could enhance the immune response because the danger signals released from ferroptotic cells may act as adjuvants for stimulating the immune system. Recently, it was shown that early, but not late, ferroptotic cancer cells release classical DAMPs  with subsequent phenotypic maturation of BMDCs . The autth stage . The est3O4-SAS@PLT) built from sulfasalazine (SAS)-loaded mesoporous magnetic nanoparticles (Fe3O4) and platelet (PLT) membrane camouflage effectively triggered ferroptosis by inhibiting system xc− and improving the efficacy of programmed cell death 1 (PD-1) immune checkpoint blockade therapy in a mouse model of metastatic tumors of murine breast cancer 4T1 [3O4-SAS@PLT repolarizes macrophages from the immunosuppressive M2 phenotype to the antitumor M1 phenotype, which effectively inhibits metastatic tumor growth. All of these studies indicate that ferroptosis can be immunogenic. Development of novel cancer immunotherapy based on ferroptosis induction is a possibility.Since iron plays a pivotal role in ferroptosis, novel strategies are focused on the construction of iron-based nanomaterials, for example, ferumoxytol , inorganncer 4T1 . That stvia regulation of GPX4 and heme oxygenase 1 (HMOX1) and exerts antitumor effects in esophageal squamous cell carcinoma cell lines and BALB/cAJcl-nu/nu mice with subcutaneously transplanted KYSE30 cells [Evidence has emerged in the last few years that PDT can also induce ferroptosis in tumor cells. For example, 5-ALA induces ferroptosis 30 cells .Studies on ferroptosis induction by PDT are closely linked with the design of third-generation PSs: nanocomplexes/nanocontainers combining PSs with pharmacological agents, PSs incorporated into liposomes, PSs conjugated with sugar molecules, monoclonal antibodies, and peptides . The devMoreover, the development of nano-platforms provides an opportunity for facilitating photodynamic reactions. For instance, to overcome the hypoxia-related limitation of PDT, oxygen-boosted PDT uses agents that increase oxygen concentration in the tumor microenvironment . ProvidiThe development of multi-modal nano-platforms also enables synergistic photothermal/photodynamic/chemodynamic cancer therapies, which have excellent anti-tumor effects, and a stronger immune response that controls the growth of both the primary and distant (untreated) tumors, as reported for murine breast cancer 4T1 in vitro and in vivo . It has Nevertheless, despite the above-mentioned advantages, the developers of nano-constructs for ferroptosis induction face several challenges, including maintaining a balance between excessive iron-induced toxicity and insufficient iron delivery. Thus, during the development of nano-constructs, one should take into account both their biocompatibility with normal and tumor cells and their ability to provide unimpeded development of ferroptosis and maintenance of the efficiency of photodynamic reactions , 171.Recent studies indicate that PDT can trigger ferroptosis together with other cell death modalities. This is especially relevant for highly resistant tumors consisting of actively proliferating cells and dormant cells that enter reversible G0 cell cycle arrest, thereby posing a risk of metastases and evasion of immunological control . Since tIII complex derived from benzothiophenylisoquinoline with imidazophenanthroline and its derivative as an ancillary ligand (IrL1 and MitoIrL2), together with a mitochondria-targeting triphenylphosphonium group to activate apoptosis [Recently developed is a photosensitizing cyclometalated Irpoptosis . Both coInduction of mixed cell death types has also been shown in another approach based on PDT and methylene blue , 175. ThInterestingly, photosens-based PDT can activate both apoptosis and ferroptosis in murine glioma GL261 cells, and the cell death has pronounced immunogenic properties . Dying cRecently published studies describing the immunogenic nature of ferroptosis support the idea that ferroptosis induction by PDT can be a powerful alternative strategy for increasing the efficacy of cancer therapy. Further insights into the interplay and synergism between PDT and ferroptosis, as well as the possibility of inducing mixed cell death modalities (ferroptosis with apoptosis and/or ferroptosis with necroptosis) may provide new possibilities for the development of novel cancer immunotherapy against resistant and highly malignant tumors.Сell-fate decisions elicited by PDT are largely dependent on the photochemical properties and biological effects of the PS, its concentration, the irradiation dose and, more importantly, on the genetic, epigenetic and phenotypic tumor profiles. High tumor heterogeneity even between tumors of the same origin and sub-classification can be one of the main causes of a large discrepancy between the responses of tumor cells to PS uptake and PDT-induced activation of cell death modalities on the one hand, and the development of tumor resistance to the therapy on the other hand. In this regard, a recent review by Aniogo and colleagues described in detail the possible molecular pathways that might be responsible for the escape of tumor cells from PDT . Among tAn equally important challenge is the development of tumor-specific markers to predict tumor sensitivity to PDT in order to select patients for PDT. Generic markers for prediction of PDT sensitivity are needed, as well as markers highly specific for each tumor type.Recent discussions at the Annual Congress of the European Society for Photodynamic Therapy (Euro-PDT) in 2020 pointed out potential markers of the efficiency of PDT-based methyl aminolaevulinic acid cream (MAL-PDT) in patients with basal cell carcinoma. These markers were immunopositivity to p53 (good patient responsiveness to PDT) and increased immunostaining of β-catenin, the expression of which is linked to tumor aggressiveness (poor patient responsiveness to PDT) . In patiClinical use of PDT began in the middle of the 20th century and has taken its place among the therapeutic tools for different types of cancer. However, since cancer remains a serious challenge for public health, there is a need to review and revise the current approaches for boosting the efficacy of tumor eradication and eliminating the risk of tumor recurrence and metastasis while maintaining the quality of patients’ lives.Looking ahead, the ideal protocol for PDT should comply with the following requirements Fig. . First aIn recent years, it has become clear that cancer cells exposed to PDT can proceed through several different cell death pathways that have either immunogenic or non-immunogenic properties. Which pathway(s) they go through determines the outcome of PDT. The variety of cell death modes make it possible to avoid cancer cell resistance to certain types of death, and particularly apoptosis and necroptosis. Following the novel concept of personalized medicine, it has become evident that PDT approaches should also focus on providing light doses based on the characteristics of the individual tumors. The use of a specific PS and combined with a specific PDT power will lead to the induction of alternative regulated forms of cell death with hallmarks of ICD. It is important to emphasize that PDT enables the use of combinations of the same PS with different irradiation regimens to trigger different cell death responses. This could be the fundamental basis for the development of PDT regimens, which should be focused on simultaneous induction of several cell death modalities, increasing treatment efficacy, and preventing the acquisition of resistance to cancer therapy. Though modern PSs can penetrate well into tumors, the most intense photodynamic reactions proceed on the tumor surface due to the limited penetration of light, which means that the activity of photodynamic reactions in cells depends on the location of the cells in the tumor. Therefore, the PDT procedure must take into account that low irradiation intensities in deep tumor layers can have a pro-tumorigenic effect resulting in the development of tumor resistance to the treatment. The use of photodynamic agents that induce regulated cell death modalities at both high and low light intensities is an attractive solution. Importantly, the cell death types in the deep layers of the tumor could differ from those on the surface, but it is highly desirable that the ICD modalities will be induced. Combining ferroptosis induction by PDT with induction of other cell death modalities could boost the efficacy of the treatment. It has been proposed that since both PDT and ferroptosis rely on the Fenton reaction, which ultimately leads to the production of lipid ROS, they can work synergistically and possibly achieve a stronger induction of cancer cell death . Further


Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer. In agreement, the blanket use of NRF2 inducers or inhibitors along with anticancer therapies cause adverse effects in some preclinical cancer models. In this review, we have summarized the levels of oxidative stress, metabolic preferences and NRF2 activity in the different stages of prostate cancer. We also propose condition specific ways to use NRF2 inducers or inhibitors along with conventional prostate cancer therapies. The significance of this review is not only to provide a detailed understanding of the mechanism of action of NRF2 to regulate oxidative stress-mediated metabolic switching by prostate cancer cells to escape the radiation, chemo, or hormonal therapies, and to grow aggressively, but also to provide a potential therapeutic method to control aggressive prostate cancer growth by stage specific proper use of NRF2 regulators. Nuclear factor erythroid 2-related factor 2 (NRF2) protein is encoded by the human NFE2L2 gene and is a member of basic leucine zipper transcription factor protein families . In an oOverall redox homeostasis helps to maintain physiological metabolism and other cellular functions. In pathological conditions, such as cancers, the metabolic rate increases to sustain the higher energy demands of rapidly proliferating cancer cells . Higher The purpose of this review is to summarize the functions by which NRF2 regulates mitochondrial health and metabolism in varying redox environments, and therapy responses in prostate cancer (PCa) and its microenvironment. PCa has been chosen as the model of this discussion because initially PCa is sensitive to therapy but in the advanced stages, PCa becomes therapy resistant, which can result in metastatic growth. The early and late forms of PCa also have different ROS environments and metabolic preferences, which reflect the different mitochondrial activity at different stages of PCa . TherefoIn this review, we will discuss the status of ROS in PCa progression, metabolic alteration, and therapy resistance. Then we will discuss on the canonical function of NRF2 in cellular defense and in mitochondrial health maintenance. Finally, we will discuss the role of NRF2 in the mitochondria-mediated alterations in PCa progression and therapy resistance.Increased oxidative stress is required for increased invasiveness in metastatic PCa B. . ProstatNormal prostate epithelial cells depend on glycolysis  and haveUnlike other cancers, PCa aggressiveness is not linearly dependent on glycolysis. Aggressive PCa cells also depend on mitochondrial oxidative phosphorylation (OXPHOS) C. L. . Normal Transformation of PCa progresses from normal prostate to benign prostate hyperplasia (BPH), to prostatic intraepithelial neoplasia (PIN), to localized PCa, to metastatic castration resistance PCa (CRPC), and neuroendocrine (NEPC) type PCa. Depending on the clinical stage, therapy options for localized PCa are active surveillance, prostatectomy, local radiotherapy, androgen deprivation therapy (ADT) and a combination of two or more of these therapies. After metastasizing to local or distant organs, the therapy options for these aggressive PCa cells are ADT and chemotherapies. Often failure of these therapies results in radioresistant, chemoresistant, CRPC and NEPC, which causes PCa related deaths. Therapies, such as, radiotherapy, kill PCa cells via ROS but the cells escape therapy-mediated cell death and become adapted to in high ROS environment, which results in relapse of the disease. Therefore, increased oxidative environment is a crucial factor for therapy resistant growth.In the early stages of PCa, the cancer is androgen sensitive. As the disease progresses, PCa becomes androgen independent, accumulates more ROS, and at the final advanced stages of PCa, reactivation of non-canonical androgen receptor (AR) signaling in CRPC, and chemical ADT resistance enhances glycolysis . TherefoAs in the case of ADT, the late stage PCa become resistant to radiotherapy as well. The degree of radioresistance depends on the internal oxidative state. Radiation causes oxidative stress in cancer cells as well as in the normal cells surrounding the tumor. Radioresistant PCa often causes aggressive transformation to NEPC and metastasis, finally resulting in death of the PCa patients. NEPC growth is dependent on mitochondrial metabolism-mediated acidic extracellular pH . RadiatiMitochondrial metabolic rewiring in chemoresistance and chemotherapy induced side effects are well reported . CisplatA major reason for therapy resistant PCa growth is cancer stem cell (CSC) proliferation, de-differentiation, and plasticity. Therefore, specific targeting of CSC would lead to enhancement of treatment efficacy and reduce the chances of tumor recurrence. CSCs rely on OXPHOS as a main source of energy production; therefore, this OXPHOS dependency can be used to selectively target CSCs in combination with PCa therapies. Treatments of PCa by OXPHOS complex I inhibitors, force PCa cells to compensate the energy need by glycolytic switch. This may reduce CSC activity during treatment resistance and increase CSC sensitivity to conventional therapies . Stem ceIn this section, we have discussed the importance and interrelationship of increased oxidative stress and mitochondrial metabolic pathways, especially preferential usage of glycolysis, OXPHOS and lipid metabolism with PCa progression and therapy resistance. From this knowledge we speculate that PCa cells and other cells in a PCa tumor microenvironment, use a potent survival mechanism to cope and prosper in this increasing oxidative stress environment as PCa progresses. NRF2 is a potential candidate as it is a master regulator of cellular defense against oxidative stress and metabolism. In the next sections, we will discuss the role of NRF2 in regulating oxidative stress, mitochondrial metabolic shifting in PCa progression and therapy resistance.NRF2 is a master regulator of cellular defense against oxidative and xenobiotic stress. NRF2, a member of the Cap’n’collar (CNC) transcription factor family and contains seven Neh (NRF2-ECH homology) domains, namely Neh1-Neh7 . The NehThe expression of NRF2 is tightly regulated. Under normal homeostatic conditions, NRF2 mRNA is constitutively expressed  and is sde-novo synthesized NRF2 is imported to the nucleus wherein it heterodimerizes with sMaf and binds to a regulatory enhancer sequence ARE; thus, promoting the expression of antioxidant and detoxifying genes and down-modulating the production of pro-inflammatory mediators  mediated nuclear export and degradation . AlternaThe BTB and CNC homology 1 (BACH1) transcription factor is a negative NRF2 competitor and molecular sensor of intracellular heme, it competes with NRF2 for its binding sites on DNA . BACH1 iNRF2 plays a key role in combating pathologic ROS formation as well as inflammatory and metabolic responses by coordinating the activity of various proteins; it induces the expression of antioxidants as well as cytoprotective genes through the regulation of multiple signaling pathways. In the next section we will discuss the role of NRF2 in mitochondrial metabolism and maintenance of overall health of the cell in increased oxidative stress in initial and advanced stages of PCa.+/NADPH ratio, mitochondrial ROS levels and ATP production can be regulated by NQO-1  and showed significant reduction of initial PCa incidence . HoweverDisruption of NRF2 activity, elevated ROS and increased DNA damage have been reported as responsible factors for the oncogenic transformation at the initial stage of human PCa . In the NRF2: The master regulator of cellular defense. Therefore, along with direct NRF2 mutations, mutations in the NRF2 regulatory genes, Keap1 and p62, also affect NRF2 function. Mutation in speckle-type POZ protein (SPOP) is common in PCa, SPOP binds to p62 and releases it from Keap1. Keap1 then becomes available for NRF2 binding, which reduces NRF2 activity. In PCa, mutated SPOP cannot bind to p62, which makes Keap1 engaged with p62 instead of NRF2, which results in oncogenic stabilization of NRF2 in PCa  is a growth promoting enzyme in PC3 cells. Suppression of PYGB reduced NRF2 signaling and increased ROS, which resulted in apoptosis . The majvia reduction of PGC1α and HIF1α activity. As a result, mitochondrial metabolism-dependent aggressive, therapy-resistant PCa growth may be controlled. However, glutathione oxidation is a crucial metabolic regulator of the pentose phosphate pathway , NRF2 modulators are being used in several active and terminated clinical trials for different cancers, including prostate cancer. We have listed the candidates in According to the There have been completed clinical trials using NRF2 inducers, such as, sulforaphane, curcumin and epigallocatechin gallate (EGCG) on prostate cancer. No data about prostate cancer reduction is available from those trials. However, there are some data published on the effect of dietary sulforaphane (broccoli sprout extract) and epigallocatechin gallate (green tea extract) on prostate cancer patients. No significant correlation of broccoli sprout extract was found with histone deacetylase activity or prostate specific markers Z. . Long teAnother crucial challenge of using NRF2 inducers or inhibitors are the tissue specific effect to induce NRF2. The canonical use of NRF2 modulators will increase NRF2 both in normal and cancer tissue, which will be beneficial for cancer tissue to grow. To overcome this clinical challenge, tissue specific inducers or inhibitors of NRF2 should be used clinically. Manganese porphyrins and β-Lapachone may be advantageous in this issue. Manganese porphyrin enhances NRF2 in the normal tissue only , which hIn PCa, mitochondrial metabolic shift plays a key role in PCa progression and therapy resistance. There have not been enough studies conducted to identify the role of NRF2 in each mitochondria-regulated step during PCa progression. Early and late stage PCa are different in terms of metabolism, oxidative environment and NRF2 activity. The role of NRF2 in the regulation of mitochondrial TCA and OXPHOS enzyme activity needs to be studied extensively in the different stages of PCa. The potential function of NRF2 activators and inhibitors with zinc accumulation and mitochondrial citrate release to inhibit oncogenic transformation of PCa, needs to be further studied. The role of NRF2 in mitochondrial dynamic changes, such as, fission, fusion, mitophagy and biogenesis of mitochondria in different stages of PCa also needs to be studied in PCa cells and in different cell types in the PCa tumor microenvironment.NRF2 activity cannot be specifically defined as cytoprotective or pro-tumorigenic in a PCa tumor environment. Many factors including the localization of NRF2 in the tumor tissue, the stages of cancer, the therapy response of the cancer, and the metabolic properties of the cancer determine the anti-tumor or pro-tumor activity of NRF2. In


JCI, Fischer et al. report on their use of genetically engineered mouse models and organoids to study the role of R-spondin 3 (RSPO3) in the stomach. RSPO3, one of the major stem cell niche factors, primarily promoted secretory differentiation in the normal stomach, but also contributed to regeneration following injury. Mechanistically, RSPO3 was upregulated in the stroma by loss of chief cells and then activated the YAP pathway in gastric stem and progenitor cells, which appeared to be critical for regeneration of the secretory lineage. These data substantially advance our understanding of the regulation of gastric stem cells and highlight a function for RSPO3 in the gastrointestinal tract, which is as the gatekeeper of secretory differentiation.The gastric oxyntic glands are maintained by gastric stem cells that continuously supply all differentiated cell types within the corpus epithelium. Stem cells are supported by stromal cells that make up the stem cell niche. In this issue of the  The stomach can be subdivided into three different regions: the antrum, the cardia, and the corpus, the latter being the acid-secreting portion that makes up the majority of the stomach. The corpus epithelium consists of the oxyntic glands that contain a variety of secretory cell types, including parietal cells secreting gastric acid, chief cells secreting digestive enzymes, and mucous neck cells secreting gastric mucins and antibacterial peptides. Similarly to gastrointestinal (GI) glands at other sites, the oxyntic glands are maintained by long-lived stem cells that have the ability of self-renewal and multipotentiality. While most GI stem cells reside near the base of glands, corpus stem cells are confined to the upper part of glands, namely the isthmus, and supply progeny bidirectionally toward both the top and base of the glands. The corpus gland base is occupied by abundant chief cells, most of which are thought to be derived from mucous neck cells located in the midglandular region. Thus, one major route of cell supply in the oxyntic glands is the downward migration starting from isthmal stem cells, in which daughter progenitors first differentiate to mucous neck cells and then later transdifferentiate to the basal chief cells .Myh11+ myofibroblasts near the gastric gland base and modulated proliferative responses to injury , was highly expressed in o injury , 3. Indeo injury . Lgr5 exJCI, Fischer et al. ..JCI, FisLgr5-DTR mice, depletion of RSPO3 was found to inhibit mucosal proliferation and regeneration, leading to delayed recovery of the chief cell population  or genetic ablation of chief cells using diphtheria toxin (DT) in pulation , 6. Impoeviously , 6. RSPOgenitors .Helicobacter pylori (Hp) infection model and found that chronic Hp infection together with RSPO3 overexpression led to robust mucosal hyperplasia and proliferation. Mechanistically, the authors concluded that RSPO3-induced mucosal regeneration and hyperproliferation depends on the activation of the yes-associated protein (YAP) pathway, which previously has been shown to be involved in intestinal stem cell activation and mucosal regeneration  are more problematic in the setting of acute injury where this expanded lineage is short-lived. Such double-positive cells, as shown again in this study, exist in the normal gastric glands as intermediate cells between neck and chief cells during the normal process of chief cell differentiation. While RSPO3 did lead to an increase in GSII+GIF+ cells, consistent with the process of expanding chief cells, the notion that RSPO3 contributes to SPEM development was not supported by studies in Rspo3-KO mice, which showed the same level of GIF+GSII+ cells as WT mice, and thus seemed inconsistent with a major role in SPEM. The data perhaps point to some other bottleneck to full chief cell differentiation. In addition, given that there are no true cancers in the models the authors used, the role of RSPO3 in gastric cancer development remains uncertain at this point , although these data need cautious interpretation. The markers used for chronic SPEM  signal impairs mucosal homeostasis, particularly following injury and in regenerative states –12, and Rspo3 did not appear to impair corpus stem cell function, overexpression of RSPO3 did induce hyperproliferation in the isthmus where Lgr5 was not highly expressed. While the authors did not investigate the mechanisms here very deeply, several clues were provided (+Lgr5– stem cells via Lgr4 (While KO of via Lgr4 , and thuThe models presented  should a


Many of the major CNS cell-type populations distributed across the different brain regions are targets for several neurotropic viruses. Numerous studies have demonstrated that viral susceptibility within the CNS is not absolute and initiates a cell-type specific antiviral defence response. Neurons, astrocytes, and microglial cells are among the major resident cell populations within the CNS and are all equipped to sense viral infection and induce a relative antiviral response mostly through type I IFN production, however, not all these cell types adopt a similar antiviral strategy. Rising evidence has suggested a diversity regarding IFN production and responsiveness based on the cell type/sub type, regional distinction and cell`s developmental state which could shape distinct antiviral signatures. Among CNS resident cell types, neurons are of the highest priority to defend against the invading virus due to their poor renewable nature. Therefore, infected and uninfected glial cells tend to play more dominant antiviral roles during a viral infection and have been found to be the major CNS IFN producers. Alternatively, neuronal cells do play an active part during antiviral responses but may adopt differential strategies in addition to induction of a typical type I IFN response, to minimize the chance of cellular damage. Heterogeneity observed in neuronal IFN responsiveness may be partially explained by their altered ISGs and/or lower STATS expression levels, however, further  The central nervous system (CNS) is an immunologically active tissue, comprising multiple cell populations which belong to different cellular lineages and work in harmony to maintain integrity and function of the CNS , 2. DespIn recent years there has been increasing evidence that region and cell-type specific antiviral responses are induced following viral invasion of the CNS, however, how innate antiviral responses in specific cell types and regions of the brain define host immune protection is not fully understood. In this review, we compare differential intervening factors which are involved in shaping distinct antiviral responses by major cell types of the CNS.The central nervous system (CNS) is a constitutive structure of brain and spinal cord. The brain is an assembly of numerous neuronal and glial cell types conserved by restrictive anatomical barriers, including choroid plexus, meninges, the blood brain barrier (BBB), and olfactory epithelium, which are also appropriate niches for viral invasion through providing an interface between cerebrospinal fluid (CSF), blood and brain parenchyma . Vertebrin vitro studies of primary cell cultures, most resident cell types within the CNS have the required host cell factors to sense viral infection and trigger multiple innate immune signaling pathways with the purpose of viral elimination (including the production of IFN); however, not many in vivo studies have been performed to identify IFN-producing cells within the CNS  infection, with no alteration in viability observed in primary rat astrocytes 14 days post infection , non-neuronal cells seem to be infected abortively, with astrocytes being more resistant than microglia . Primarystration . Additiostration . In the stration . Additiostration . The divstration .Togaviridae family, which causes neuronal cell-death via induced apoptosis. However, neuronal maturation provides protection from viral induced apoptosis, and these cells become resistant to SINV infection , an Alphavirus from the nfection . In agrenfection . Howevernfection , and mitnfection . The disHerpesviridae family that can cause persistent infection in neuronal and glial cells within the CNS. Brain cultures obtained from mouse barin, selectively enriched in either glia or neurons showed higher number of murine cytomegalovirus (MCMV) infected astrocytes compared to neurons and microglia, this ratio changed over time with higher numbers of neurons showing evidence of infection after 18 hours, in vitro and in vivo. In the same study, although MCMV showed no absolute brain cell preference, cortical radial glial cells were the most compromised cell types during infection while striatal neurons demonstrated higher incidence of infection compared to glial cells in the same brain region , triggering several antiviral signaling pathways Table 2.Virus infection within specific cells of the CNS triggers activation of several families of pattern recognition receptors (PRRs). Viral nucleic acid is detected through a network of PRRs, including Toll-like receptor (TLR), Retinoic acid-inducible gene (RIG)-I-like receptors, and DNA sensors, expressed by a wide variety of cell types within the CNS. Detection of conserved PAMPs by PRRs activates antiviral signaling pathways in the CNS by promoting transcriptional activation of genes that direct cellular immunity against viruses subsequently leading to secretion of antiviral cytokines such as type-I and -III IFNs and expression of antiviral ISGs . It is avia an extracellular domain giving rise to several signaling pathways downstream. Intracellular TLRs  mainly recognize viral nucleic acid, including the recognition of viral double-strand RNAs (TLR 3), single-strand RNAs (TLR 7 & 8) and CpG oligodeoxynucleotide (TLR 9). RLRs rDNA viruses are mainly recognized by the cytoplasmic viral DNA sensor, cGAMP synthase (cGAS), which signals through an adaptor molecule, stimulator of IFN genes (STING). STING recruits TBK1, and this results in the activation and nuclear translocation of IRF3 and induction of type I IFNs. Most studies performed in this area are around HSV-1 infection, showing higher viral load and cell death in STING-deficient mice along with a failure in type I IFN production [reviewed in ]. It hasInfection by many viruses is associated with type-I IFN production, particularly in the early stages of infection. However, viral nucleic acid sensing pathways and the main protein players involved can vary among different brain cell types, and therefore may play a role in shaping a cell-type specific IFN response within different brain cell populations . It is cin vivo  2 and JAK1. The STATs phosphorylation with the association of IRF9 then leads to form a transcriptional activator complex which subsequently is translocated to the nucleus and binds to the promoter regions of IFN-stimulated genes (ISGs), and activates their transcription  pathway . IFN bincription . It is ccription Figure 3Astrocytes are considered the main IFN-β producers of the brain in many cases of neurotropic viral infections, including RABV, TMEV, and VSV, and have been established to sense viral components in a TLR3/RIG-I/MDA-5 mediated pathway leading to IFN-β induction in theses cell types , 12. ThiMicroglia, another glial cell type, with astrocytes are considered the main source of IFN-β within the brain in many virus infections , 78. Micvia the olfactory route (Unlike neurons, glial cells across different regions of the CNS have been demonstrated to be capable of inducing type I IFN responses against viral infection in a mouse model, and don’t appear to be impacted by subtypes or developmental states . Howeverry route . Additiory route .via upregulation of IRF7, and to subsequently respond to type I IFNs by Mx1 upregulation, however, the ability for neurons to produce type I IFN was only observed in a small proportion of the infected neuronal population (Although several studies have presented neurons as being both IFN-α/IFN-β producers and responders, this does not appear to apply to all neuronal cell populations equally following viral infection , 39–41. pulation .Neuronal maturation state has also been demonstrated to be an important factor in the ability of these cells to respond to viral infection, with neurons from human cerebral organoids showing differential responses to LACV infection based on their maturation state. Although both progenitor and committed neurons were susceptible to LACV, committed neurons underwent apoptosis following infection, which was hypothesized to be due to their lower expression level of ISGs . The corNeurons are capable of inducing sufficient innate immune responses following viral infection, however, these responses seem to vary depending on the virus, neuronal cell line and neuronal maturation , 39–41. Unlike glial cells with their strong ISGs repertoire, some neuronal populations express very low basal level of IFN and ISGs, therefore may differ in their responsiveness to type I IFN. In this regard, some neurons have been shown to either respond poorly to IFN treatment and/or preferentially choose autophagy as their antiviral mode of action. For instance, hippocampal CA1, CA2 and CA3 neurons display differential MX1 expression in response to IFN treatment , and dorAlmost all CNS resident cell types contribute to type I IFN production following virus invasion; however, not all these cells respond similarly to IFNs which may subsequently define the induced antiviral response of a specific cell type and the outcome of the host-virus survival challenge Figure 3via a PI3K/AKT/mTORC1 signaling pathway . In thiin vitro studies have extended our knowledge surrounding cell type specific responses in cells of the CNS, the very recent advent of single cell transcriptomics should allow a better picture of cell type specific anti-viral responses during in vivo infection models. Unfortunately, to date, this technology has not been used to its full potential for in vivo studies of virus infection in the brain. This is mainly due to the challenging nature of separating out individual cell types, where they have been found to be lost in the process of dissociation from intact tissue into single cell suspensions [reviewed in (Although iewed in ].Despite the challenges associated with single cell transcriptomics in the brain, great efforts have been made in resolving regional cell type landscapes of mainly homogeneous cell populations within the CNS during virus infection. For example, transcriptional changes in the mouse dorsal raphe nucleus following intracranial injection of RABV revealed that the differential cell types varied in their type I and II IFN responses, with these responses being mainly mediated by a small subset of microglial cells . Additioin vivo; and how this may differ regionally.Given there are only a handful of studies to look at the single cell transcriptome of the brain tissues following infection, and these studies have not yet looked at the full cellular landscape of the brain during a viral infection event, there is still much to learn. Lessons could be taken from alternate fields, where cellular landscapes have been sourced from individual regions of the brain to address the gap in our knowledge surrounding which cell types/cell subsets are the main drivers of immune responses within the CNS Most cell types of the CNS are equipped to sense viral infection and take an active and unique role in antiviral strategies that protect themselves, as well as bystander cells by being both type I IFN responsive and productive. However, not all cell types are equally susceptible to viral infection, with differential CNS cell types adopting distinct antiviral strategies to defend against viral infection within its own microenvironment, which defines the outcome of the viral infection. In this context, although glial cells are major type I IFN producers and responders due to their stronger expression of STAT and ISG repertoires, astrocytes tend to adopt a more responsive role with microglial cells being more productive, and potentially acting as an alarming signal for adaptive immunity, driving major anti-inflammatory roles during viral infection . In contin vitro or ex vivo manner. The advent of improved single cell analysis, and the continued advancement in the space of single cell proteomics, metabolomics and lipidomics is likely to reveal novel insights into how the cells of the CNS act collaboratively during in vivo viral infections, providing an improved knowledge of intercellular communication towards design of novel therapeutics to combat viral infection of the CNS.Our understanding of the role of individual cells of the CNS in mounting a protective antiviral response is still in its infancy, with many conclusions derived from studies only involving individual cell types from variable origins in either an ZT wrote the manuscript. All remaining authors researched data for the article, made substantial contributions to the discussion of the content and reviewed and/or edited the manuscript before submission. All authors contributed to the article and approved the submitted version.ZT is supported by a Australian Government Research Training Program Scholarship.BioRender.com for allowing us to create the figures throughout this review.We thank The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The article discusses particular circumstances of acute coronary syndrome (ACS) in patients with type 2 diabetes (T2D). In addition, the available literature data and clinical guidelines reflecting the role of hypoglycemic therapy as a cardioprotection factor in ACS are analyzed. The article considers possible protective molecular mechanisms of various groups of drugs in ischemic cardiomyocytes. Nowadays, cardiovascular diseases affect approximately 32.2% of all patients with type 2 diabetes (T2D) and are currently the main cause of death among people with type 2 diabetes . HyperglRisk factors for the development and progression of ACS are known, but the exact pathophysiological mechanisms underlying myocardial infarction (MI) in diabetes are unknown .It is known that diabetes is a predictor of abnormal progression of ACS. The peculiarity of its clinical symptoms in patients with type 2 diabetes is a pain syndrome that is less severe than usual, which leads to abnormal symptoms or painless myocardial ischemia. This phenomenon can be explained by autonomic neuropathy, which leads to the increased threshold of ischemic pain perception . DiabetiPatients with abnormal clinical picture are less likely to have a diagnosis of confirmed MI at the time of admission to the hospital; and they have a higher level of in-hospital mortality than patients complaining about their chest pain. Despite abnormal symptoms, these patients do not differ substantially from those with ACS-type chest pain, increased levels of troponins or severity of coronary stenosis . MortaliThe metabolism is almost entirely based on fatty acids in a diabetic. In ACS with insulin resistance, the cellular metabolism of the heart becomes completely dependent on fatty acids, which increases the oxygen demand of the cells, followed by cell necrosis and apoptosis. This partly explains the higher mortality after myocardial infarction . ApoptotEndothelial dysfunction in diabetic patients leads to increased proliferation of smooth muscle cells after vascular injury. Thus, patients with T2DM are most likely to experience restenosis after percutaneous coronary intervention. The process of restenosis begins very early (one to three months after coronary angioplasty) . High adGlucose control is an important factor in the management of ACS in diabetic patients. Patients with diabetes presenting with hyperglycemia (≥10–11 mmol/L 180–198 mg/dL]) in the setting of an acute MI have been found to have an increased risk of in-hospital mortality  [8 mg/dL) One of the glucometabolic strategies in ACS is associated with the infusion of insulin, glucose and potassium (GIK). It was believed that the simultaneous administration of potassium and insulin reduces the risk of ventricular arrhythmias, and insulin facilitates the transport of potassium into the cell. Glucose provides a more efficient energy metabolism than free fatty acids or ketone bodies. However, recent large studies, CREATE-ECLA or OASIS-6 GIK, have shown that GIK infusion has no effect on mortality, cardiac arrest, or cardiogenic shock in ACS. Moreover, it has been shown that such therapy may even be harmful in the early stages of ACS due to hyperkalemia. Another important problem with the GIK concept is explained in the CREATE-ECLA study: despite insulin administration, mean glucose levels increased during therapy from 162 mg/dL (9 mmol/L) to 187 mg/dL (10.4 mmol/L) after 6 h of the introduction of GIK. Since glucose levels are independently associated with mortality, a glucometabolic strategy that raises her glucose levels and therefore goes in the wrong direction can be interpreted as a positive result for a testable hypothesis .The impact of glycemic control on cardiovascular outcomes and the best approach to treat hyperglycemia during and following an acute cardiovascular event remain a matter of debate in resent time .In the treatment of ACS affected by type 2 diabetes, due consideration should be given to the fact that patients take a large number of various drugs. In the American cross-examination of 875 patients with type 2 diabetes, half of the respondents said they used to take at least seven prescription drugs, and 49% said they used to take two or more antihyperglycemic drugs. In addition to antihyperglycemic drugs, most often the respondents used to take antihypertensive drugs (71% of respondents) and drugs for hyperlipidemia (53%) [Metformin is the most commonly prescribed antihyperglycemic drug of the biguanide class that is considered the “gold standard” for the treatment of T2D. At the moment, it is preferable to prescribe metformin as initial treatment for those patients who have not previously taken hypoglycemic therapy; and then they shall take metformin as long as possible. The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) call metformin a drug of choice for glycemic control of diabetes mellitus . MetformExperimental data indicate metformin’s favorable effects on the left ventricular function. These effects are largely mediated by activation of the ATP-activated protein kinase, which plays a key role in such biochemical processes as glycolysis, oxidative phosphorylation of fatty acids, mitochondrial biogenesis, and glucose uptake. These processes contribute significantly to increase ATP levels and to restore myocardial contractility. AMPK also activates endothelial nitric oxide synthase (eNOS) and promotes autophagy, thereby preventing inflammation and necrocytosis. In diabetic patients with ST-elevation myocardial infarction (STEMI), retrospective analyses showed that their treatment with metformin is associated with reduced necrotic size as compared with patients not receiving metformin, implicating beneficial effects beyond glucose control. A recent GIPS-III randomized trial showed that metformin may improve left ventricular function following STEMI even in patients without diabetes . HoweverThe hypoglycemic effect of sulfonylurea drugs is based on the stimulation of pancreatic β-cells, which leads to increased endogenous insulin secretion. On the β-cell membrane, the drug molecule binds to the receptor associated with ATP-dependent potassium channels, which results in the β-cell insulin release. However, with prolonged treatment, stimulating effects of these drugs decline. It is assumed that this phenomenon is due to a drop in the number of receptors on the surface of β-cells . In the Dipeptidyl peptidase 4 inhibitors (DPP4i) are a class of drugs that prevent degradation of incretin hormones ) and increase insulin secretion, and also inhibit glucagon release . The groAn improvement in beta-cell function may be of prognostic importance in patients with MI. GLP-1 has beneficial effects on the myocardium by increasing myocardial glucose uptake, improving endothelial function and potentially reducing infarct size; it also has anti-inflammatory and anti-atherogenic properties . The mecRandomized studies demonstrated inconsistent results regarding the benefit of intravenous insulin for glycemic control in patients with ACS .In the heart, insulin controls glucose transport, glycolytic speed, glycogen synthesis, growth, contractility of cardiomyocytes and their survival, acting mainly through insulin receptor subunit (IRS-1/2) proteins, phosphoinositide-3-kinase (PI3K), Akt (5) and the mammalian target of rapamycin (mTOR) signaling pathway . HyperglIn the available literature, we did not find any information on the effect of these drugs having glycosuric effect on the prognosis of ACS in in diabetics . HoweverThus, for the present, the problem of using hypoglycemic therapy to reduce the risk of cardiovascular complications in patients with T2D and ACS persists. The effect of metformin on early and long-term clinical outcomes of ACS is not well known, insulin therapy is associated with potentially dangerous hypoglycemia in ACS, and the use of other antihyperglycemic drugs to prevent cardiovascular events in the above category of patients remains understudied.