Also published as: B Hao, F Hao, Fengjie Hao, Ge, Hao, Li, Hao, Liang Hao, M Hao, M. Hao, T. Hao, Wu, Hao, Xiaojuan Hao, Xue Hao, Yingying Hao, Z Hao, Zhi-feng Hao
Liquid-liquid phase separation (LLPS) is a fundamental biophysical process driving the formation of dynamic biomolecular condensates, which spatially organize cellular biochemistry without membrane de Show more
Liquid-liquid phase separation (LLPS) is a fundamental biophysical process driving the formation of dynamic biomolecular condensates, which spatially organize cellular biochemistry without membrane delimitation. These condensates arise from multivalent, weak interactions among intrinsically disordered proteins, modular interaction motifs, and RNA scaffolds, enabling highly tunable and reversible compartmentalization of biomolecules. This phase behavior regulates critical cellular functions such as gene expression, signal transduction, and stress response, while its dysregulation contributes to pathological aggregation and disease. Recent advances leverage LLPS principles to design synthetic condensates with controllable composition, properties, and activities. Combining structural insights, quantitative phase behavior, and synthetic biology tools, engineered condensates have been developed for enhanced catalysis, metabolic control, targeted drug delivery, and biosensing. This review summarizes the molecular mechanisms, design strategies, and translational prospects of LLPS-mediated condensates, thereby paving the way for future exploration at the interface of cellular biophysics and bioengineering. Show less
Combining single-cell parallel profiling of genome conformation, histone modifications, chromatin accessibility and gene expression reveals dynamics and intranuclear spatial clustering of epigenome pr Show more
Combining single-cell parallel profiling of genome conformation, histone modifications, chromatin accessibility and gene expression reveals dynamics and intranuclear spatial clustering of epigenome profiles, enabling sophisticated analysis of the regulatory landscape across cell types and tissues. Show less
Zinc is a crucial element in cellular processes, and its homeostasis has intricate relationships with the initiation, progression, and therapeutic intervention of cancer. Activation of the cyc Show more
Zinc is a crucial element in cellular processes, and its homeostasis has intricate relationships with the initiation, progression, and therapeutic intervention of cancer. Activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been proven to be an effective strategy for cancer immunotherapy. Herein, we report four phosphorescent iridium complexes (Ir1–Ir4) with zinc chelating ligands. Among them, Ir1 can bind and image mitochondrial chelatable zinc ions via phosphorescence-lifetime responses, consequently modulating the expression of zinc-regulatory proteins. Furthermore, the in situ formed heteronuclear metal complex Ir1-Zn2 shows nuclease mimetic activities, capable of hydrolyzing mitochondrial DNA (mtDNA) to release mtDNA fragments for the activation of the cGAS-STING pathway. In conclusion, we designed a mitochondria-targeting phosphorescent Ir(III) complex with dual functions in dysregulation of zinc homeostasis and generation of nuclease in situ, which provides an innovative approach to stimulate the cGAS-STING pathway.
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Colorectal cancer (CRC) remains a significant oncological challenge, being among the foremost contributors to cancer-related mortality worldwide. This review summarizes our current knowledge regarding Show more
Colorectal cancer (CRC) remains a significant oncological challenge, being among the foremost contributors to cancer-related mortality worldwide. This review summarizes our current knowledge regarding how metabolic reprogramming, specifically the Warburg effect, contributes to CRC pathobiology and explores its therapeutic relevance. Metabolic reprogramming in CRC is characterized by a shift from oxidative phosphorylation to glycolysis, termed the Warburg effect. Driven by the tumor microenvironment (TME), this adaptation enhances cancer cell proliferation through accelerated ATP generation, biosynthesis support, and redox balance. Key glycolytic enzymes, namely hexokinase, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase are now prioritized as therapeutic targets in CRC treatment strategies. Diagnostic modalities utilizing CRC’s altered metabolism such as 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and metabolomic analysis of circulating metabolites, improved early detection through enhanced sensitivity and specificity. These approaches reveal CRC’s distinct metabolic signatures, enabling precise disease stratification and management. Therapeutic strategies targeting the EMP pathway show preclinical efficacy in overcoming CRC-associated chemoresistance and radioresistance. Modulation of EMP-regulating pathways (AKT, AMPK, mTOR) provides additional therapeutic opportunities. However, CRC’s metabolic heterogeneity demands multi-targeted approaches. The development of targeted therapies must consider the potential off-target effects on normal tissues that rely on EMP, necessitating a careful balance between therapeutic efficacy and safety. In summary, this review underscores the complexity of metabolic reprogramming in CRC and the need for a nuanced approach to target these pathways effectively. Subsequent investigations should prioritize defining tumor-selective metabolic vulnerabilities and engineering multi-pathway interventions that spare normal tissues, ultimately advancing therapeutic precision in CRC management. 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, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identif Show more
Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment. Show less
Developing a new generation of increased energy, stability, and easily applicable N-rich energetic materials to replace RDX and HMX has posed significant challenges over the past decade. This Show more
Developing a new generation of increased energy, stability, and easily applicable N-rich energetic materials to replace RDX and HMX has posed significant challenges over the past decade. This work presents the design and synthesis of a series of novel N-rich energetic materials (N1 to N3 series) based on the triazole–tetrazole system. Among these, the N3 series demonstrates exceptional detonation performance and stability. It is noteworthy that the N3-3 molecule has achieved the best overall performance among N-rich energetic materials, with an onset decomposition temperature of 302 °C and a detonation velocity of 9341 m s−1, which significantly surpasses that of HMX. Additionally, structural studies of the N1 molecule reveal that the positioning effect of the nitro group and steric hindrance within the molecule disrupt the planar characteristics of the triazole–tetrazole system. In contrast, the amino group in the N3 series enhances molecular planarity, facilitating the formation of large conjugated systems and extensive hydrogen bond networks in N-rich energetic materials. This approach effectively enhances the stability of energetic material molecules and offers valuable insights for the development and design of stable N-rich energetic compounds.
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For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism t Show more
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. 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
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
The task of drug-target interaction prediction holds significant importance in pharmacology and therapeutic drug design. In this paper, we present FRnet-DTI, an auto-encoder based feature manipulation Show more
The task of drug-target interaction prediction holds significant importance in pharmacology and therapeutic drug design. In this paper, we present FRnet-DTI, an auto-encoder based feature manipulation and a convolutional neural network based classifier for drug target interaction prediction. Two convolutional neural networks are proposed: FRnet-Encode and FRnet-Predict. Here, one model is used for feature manipulation and the other one for classification. Using the first method FRnet-Encode, we generate 4096 features for each of the instances in each of the datasets and use the second method, FRnet-Predict, to identify interaction probability employing those features. We have tested our method on four gold standard datasets extensively used by other researchers. Experimental results shows that our method significantly improves over the state-of-the-art method on three out of four drug-target interaction gold standard datasets on both area under curve for Receiver Operating Characteristic (auROC) and area under Precision Recall curve (auPR) metric. We also introduce twenty new potential drug-target pairs for interaction based on high prediction scores. The source codes and implementation details of our methods are available from https://github.com/farshidrayhanuiu/FRnet-DTI/ and also readily available to use as an web application from http://farshidrayhan.pythonanywhere.com/FRnet-DTI/ . Show less