Also published as: B.B. Patel, Bhoomika M Patel, Bhumik Patel, D Patel, DJ Patel, DN Patel, H Patel, HR Patel, Hiral Patel, J. Patel, Jagdish S. Patel, Khushbu Patel, M Patel, Mohan N. Patel, N Patel, R Patel, RS Patel, RT Patel, Rajanikant Patel, SA Patel, SB Patel, SJ Patel, SM Patel
Abstract The negatively charged aminophospholipid, phosphatidylserine (PS), is typically restricted to the inner leaflet of the plasma membrane under normal, healthy physiological conditions. PS is ir Show more
Abstract The negatively charged aminophospholipid, phosphatidylserine (PS), is typically restricted to the inner leaflet of the plasma membrane under normal, healthy physiological conditions. PS is irreversibly externalized during apoptosis, where it serves as a signal for elimination by efferocytosis. PS is also reversibly and transiently externalized during cell activation such as platelet and immune cell activation. These events associated with physiological PS externalization are tightly controlled by the regulated activation of flippases and scramblases. Indeed, improper regulation of PS externalization results in thrombotic diseases such as Scott Syndrome, a defect in coagulation and thrombin production, and in the case of efferocytosis, can result in autoimmunity such as systemic lupus erythematosus (SLE) when PS-mediated apoptosis and efferocytosis fails. The physiological regulation of PS is also perturbed in cancer and during viral infection, whereby PS becomes persistently exposed on the surface of such stressed and diseased cells, which can lead to chronic thrombosis and chronic immune evasion. In this review, we summarize evidence for the dysregulation of PS with a main focus on cancer biology and the pathogenic mechanisms for immune evasion and signaling by PS, as well as the discussion of new therapeutic strategies aimed to target externalized PS. We posit that chronic PS externalization is a universal and agnostic marker for diseased tissues, and in cancer, likely reflects a cell intrinsic form of immune escape. The continued development of new therapeutic strategies for targeting PS also provides rationale for their co-utility as adjuvants and with immune checkpoint therapeutics. Show less
Tumor microenvironment (TME) denotes the non-cancerous cells and components presented in the tumor, including molecules produced and released by them. Interactions between cancer cells, immune cells, Show more
Tumor microenvironment (TME) denotes the non-cancerous cells and components presented in the tumor, including molecules produced and released by them. Interactions between cancer cells, immune cells, stromal cells, and the extracellular matrix within the TME create a dynamic ecosystem that can either promote or hinder tumor growth and spread. The TME plays a pivotal role in either promoting or inhibiting tumor growth and dissemination, making it a critical factor to consider in the development of effective cancer therapies. Understanding the intricate interplay within the TME is crucial for devising effective cancer therapies. Combination therapies involving inhibitors of immune checkpoint blockade (ICB), and/or chemotherapy now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment. Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. Cellular and acellular components in tumor microenvironment can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Components in the TME can reprogram tumor behavior and influence responses to treatments, facilitating immune evasion, nutrient deprivation, and therapeutic resistance. Moreover, the TME can influence angiogenesis, promoting the formation of blood vessels that sustain tumor growth. Notably, the TME facilitates immune evasion, establishes a nutrient-deprived milieu, and induces therapeutic resistance, hindering treatment efficacy. A paradigm shift from a cancer-centric model to a TME-centric one has revolutionized cancer research and treatment. However, effectively targeting specific cells or pathways within the TME remains a challenge, as the complexity of the TME poses hurdles in designing precise and effective therapies. This review highlights challenges in targeting the tumor microenvironment to achieve therapeutic efficacy; explore new approaches and technologies to better decipher the tumor microenvironment; and discuss strategies to intervene in the tumor microenvironment and maximize therapeutic benefits. Graphical Abstract Show less
Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite sig Show more
Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia-inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient-deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor-associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC. Show less
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical inv Show more
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies. Show less
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000 Show more
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000, accounting for 10% of all cancer deaths worldwide. Accordingly, there is a vast amount of ongoing research aiming to find new and improved treatment modalities for CRC that can potentially increase survival and decrease overall morbidity and mortality. Current management strategies for CRC include surgical procedures for resectable cases, and radiotherapy, chemotherapy, and immunotherapy, in addition to their combination, for non-resectable tumors. Despite these options, CRC remains incurable in 50% of cases. Nonetheless, significant improvements in research techniques have allowed for treatment approaches for CRC to be frequently updated, leading to the availability of new drugs and therapeutic strategies. This review summarizes the most recent therapeutic approaches for CRC, with special emphasis on new strategies that are currently being studied and have great potential to improve the prognosis and lifespan of patients with CRC. Show less
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, Show more
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer. Show less
Uncoupling proteins (UCPs) are identified as carriers of proton ions between the mitochondrial inner membrane and the mitochondrial matrix. ATP is mainly generated through oxidative phosphorylation in Show more
Uncoupling proteins (UCPs) are identified as carriers of proton ions between the mitochondrial inner membrane and the mitochondrial matrix. ATP is mainly generated through oxidative phosphorylation in mitochondria. The proton gradient is generated across the inner mitochondrial membrane and the mitochondrial matrix, which facilitates a smooth transfer of electrons across ETC complexes. Until now, it was thought that the role of UCPs was to break the electron transport chain and thereby inhibit the synthesis of ATP. UCPs allow protons to pass from the inner mitochondrial membrane to the mitochondrial matrix and decrease the proton gradient across the membrane, which results in decreased ATP synthesis and increased production of heat by mitochondria. In recent years, the role of UCPs in other physiological processes has been deciphered. In this review, we first highlighted the different types of UCPs and their precise location across the body. Second, we summarized the role of UCPs in different diseases, mainly metabolic disorders such as obesity and diabetes, cardiovascular complications, cancer, wasting syndrome, neurodegenerative diseases, and kidney complications. Based on our findings, we conclude that UCPs play a major role in maintaining energy homeostasis, mitochondrial functions, ROS production, and apoptosis. Finally, our findings reveal that mitochondrial uncoupling by UCPs may treat many diseases, and extensive clinical studies are required to meet the unmet need of certain diseases. Show less
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly i Show more
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly important role in biomedical research ranging from subcellular level to individual level. The unique properties of BICAs, including expression by cells as reporters and specific genetic modification, facilitate various in vitro and in vivo studies, such as quantification of gene expression, observation of protein interactions, visualization of cellular proliferation, monitoring of metabolism, and detection of dysfunctions. Furthermore, in human body, BICAs are remarkably helpful for disease diagnosis when the dysregulation of these agents occurs and can be detected through imaging techniques. There are various BICAs matched with a set of imaging techniques, including fluorescent proteins for fluorescence imaging, gas vesicles for ultrasound imaging, and ferritin for magnetic resonance imaging. In addition, bimodal and multimodal imaging can be realized through combining the functions of different BICAs, which helps overcome the limitations of monomodal imaging. In this review, the focus is on the properties, mechanisms, applications, and future directions of BICAs. Show less
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potenti Show more
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potential side-effects. Bioinformatic approaches, advances in machine learning techniques and the increasing deposition of high-throughput data in public databases have significantly contributed to recent advances in the field, but it is not straightforward to decide which data and methods are most suitable to use in a given case. In this review, we focus on these methods and data and their applications in generating MoA hypotheses for subsequent experimental validation. We discuss compound-specific data such as -omics, cell morphology and bioactivity data, as well as commonly used supplementary prior knowledge such as network and pathway data, and provide information on databases where this data can be accessed. In terms of methodologies, we discuss both well-established methods (connectivity mapping, pathway enrichment) as well as more developing methods (neural networks and multi-omics integration). Finally, we review case studies where the MoA of a compound was successfully suggested from computational analysis by incorporating multiple data modalities and/or methodologies. Our aim for this review is to provide researchers with insights into the benefits and drawbacks of both the data and methods in terms of level of understanding, biases and interpretation – and to highlight future avenues of investigation which we foresee will improve the field of MoA elucidation, including greater public access to -omics data and methodologies which are capable of data integration. Show less
Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTO Show more
Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells. Show less
Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss Show more
Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss-of-function mutations in ADAR p150 allow persistent activation of the interferon system by Alu dsRNAs and are causal for Aicardi-Goutières Syndrome. Heterodimers of ADAR and DICER1 regulate the switch from RNA- to protein-centric immunity. Loss of DICER1 function produces age-related macular degeneration, a different type of Alu-mediated disease. The overlap of Z-forming sites with those for the signal recognition particle likely limits invasion of primate genomes by Alu retrotransposons. Show less
Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in Show more
Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoter‐proximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function. Show less
BACKGROUND: Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic ac Show more
BACKGROUND: Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic acidurias. In the past decade, the same tricarboxylic acid cycle metabolites have been implicated and studied in cancer. The accumulation of these metabolites in certain cancers not only serves as a biomarker but also directly contributes to cellular transformation, therefore earning them the designation of oncometabolites.
CONTENT: D-2-hydroxyglutarate, L-2-hydroxyglutarate, succinate, and fumarate are the currently recognized oncometabolites. They are structurally similar and share metabolic proximity in the tricarboxylic acid cycle. As a result, they promote tumorigenesis in cancer cells through similar mechanisms. This review summarizes the currently understood common and distinct biological features of these compounds. In addition, we will review the current laboratory methodologies that can be used to quantify these metabolites and their downstream targets.
SUMMARY: Oncometabolites play an important role in cancer biology. The metabolic pathways that lead to the production of oncometabolites and the downstream signaling pathways that are activated by oncometabolites represent potential therapeutic targets. Clinical laboratories have a critical role to play in the management of oncometabolite-associated cancers through development and validation of sensitive and specific assays that measure oncometabolites and their downstream effectors. These assays can be used as screening tools and for follow-up to measure response to treatment, as well as to detect minimal residual disease and recurrence. Show less
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence Show more
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less
AIMS: Gastro-resistant dimethyl fumarate (DMF) is an oral therapeutic indicated for the treatment of relapsing multiple sclerosis. Recent data suggest that a primary pharmacodynamic response to DMF tr Show more
AIMS: Gastro-resistant dimethyl fumarate (DMF) is an oral therapeutic indicated for the treatment of relapsing multiple sclerosis. Recent data suggest that a primary pharmacodynamic response to DMF treatment is activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway; however, the gene targets modulated downstream of NRF2 that contribute to DMF-dependent effects are poorly understood.
RESULTS: Using wild-type and NRF2 knockout mice, we characterized DMF transcriptional responses throughout the brain and periphery to understand DMF effects in vivo and to explore the necessity of NRF2 in this process. Our findings identified tissue-specific expression of NRF2 target genes as well as NRF2-dependent and -independent gene regulation after DMF administration. Furthermore, using gene ontology, we identified common biological pathways that may be regulated by DMF and contribute to in vivo functional effects.
INNOVATION: Together, these data suggest that DMF modulates transcription through multiple pathways, which has implications for the cytoprotective, immunomodulatory, and clinical properties of DMF.
CONCLUSION: These findings provide further understanding of the DMF mechanism of action and propose potential therapeutic targets that warrant further investigation for treating neurodegenerative diseases. Antioxid. Redox Signal. 24, 1058-1071. Show less