Drug repurposing for cancer therapy.

Cancer, a complex and multifactorial disease, presents a significant challenge to global health. Despite significant advances in surgical, radiotherapeutic and immunological approaches, which have improved cancer treatment outcomes, drug therapy continues to serve as a key therapeutic strategy. However, the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects, and thus there remains a critical need to develop novel cancer therapeutics. One promising strategy that has received widespread attention in recent years is drug repurposing: the identification of new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective, proven to be safe, and can significantly expedite the drug development process due to their already established safety profiles. In light of this, the present review offers a comprehensive overview of the various methods employed in drug repurposing, specifically focusing on the repurposing of drugs to treat cancer. We describe the antitumor properties of candidate drugs, and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment. In addition, we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery. We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen. To conclude, we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

MG53/TRIM72: multi-organ repair protein and beyond.

MG53, a member of the tripartite motif protein family, possesses multiple functionalities due to its classic membrane repair function, anti-inflammatory ability, and E3 ubiquitin ligase properties. Initially recognized for its crucial role in membrane repair, the therapeutic potential of MG53 has been extensively explored in various diseases including muscle injury, myocardial damage, acute lung injury, and acute kidney injury. However, further research has revealed that the E3 ubiquitin ligase characteristics of MG53 also contribute to the pathogenesis of certain conditions such as diabetic cardiomyopathy, insulin resistance, and metabolic syndrome. Moreover, recent studies have highlighted the anti-tumor effects of MG53 in different types of cancer, such as small cell lung cancer, liver cancer, and colorectal cancer; these effects are closely associated with their E3 ubiquitin ligase activities. In summary, MG53 is a multifunctional protein that participates in important physiological and pathological processes of multiple organs and is a promising therapeutic target for various human diseases. MG53 plays a multi-organ protective role due to its membrane repair function and its exertion of anti-tumor effects due to its E3 ubiquitin ligase properties. In addition, the controversial aspect of MG53's E3 ubiquitin ligase properties potentially causing insulin resistance and metabolic syndrome necessitates further cross-validation for clarity.

Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.

Cholesterol is crucial for cell survival and growth, and dysregulation of cholesterol homeostasis has been linked to the development of cancer. The tumor microenvironment (TME) facilitates tumor cell survival and growth, and crosstalk between cholesterol metabolism and the TME contributes to tumorigenesis and tumor progression. Targeting cholesterol metabolism has demonstrated significant antitumor effects in preclinical and clinical studies. In this review, we discuss the regulatory mechanisms of cholesterol homeostasis and the impact of its dysregulation on the hallmarks of cancer. We also describe how cholesterol metabolism reprograms the TME across seven specialized microenvironments. Furthermore, we discuss the potential of targeting cholesterol metabolism as a therapeutic strategy for tumors. This approach not only exerts antitumor effects in monotherapy and combination therapy but also mitigates the adverse effects associated with conventional tumor therapy. Finally, we outline the unresolved questions and suggest potential avenues for future investigations on cholesterol metabolism in relation to cancer.

Diapause-like Drug-Tolerant Persister State: The Key to Nirvana Rebirth.

Cancer is one of the leading causes of death in the world. Various drugs have been developed to eliminate it but to no avail because a tumor can go into dormancy to avoid therapy. In the past few decades, tumor dormancy has become a popular topic in cancer therapy. Recently, there has been an important breakthrough in the study of tumor dormancy. That is, cancer cells can enter a reversible drug-tolerant persister (DTP) state to avoid therapy, but no exact mechanism has been found. The study of the link between the DTP state and diapause seems to provide an opportunity for a correct understanding of the mechanism of the DTP state. Completely treating cancer and avoiding dormancy by targeting the expression of key genes in diapause are possible. This review delves into the characteristics of the DTP state and its connection with embryonic diapause, and possible treatment strategies are summarized. The authors believe that this review will promote the development of cancer therapy.

Midnolin-proteasome pathway for protein degradation.

Overexpression of immediate-early genes (IEGs) has been linked to was associated with cancer progression and prognosis. In a recent study, Gu et al. reported the midnolin-proteasome pathway, a novel ubiquitin-independent proteasomal degradation. 1 The study provided the mechanism of rapid degradation for nuclear proteins with high unsteadiness. Targeting the midnolin-proteasome pathway might be beneficial for cancer therapy.

Bioelectronic medicine potentiates endogenous NSCs for neurodegenerative diseases.

Neurodegenerative diseases (NDs) are commonly observed and while no therapy is universally applicable, cell-based therapies are promising. Stem cell transplantation has been investigated, but endogenous neural stem cells (eNSCs), despite their potential, especially with the development of bioelectronic medicine and biomaterials, remain understudied. Here, we compare stem cell transplantation therapy with eNSC-based therapy and summarize the combined use of eNSCs and developing technologies. The rapid development of implantable biomaterials has resulted in electronic stimulation becoming increasingly effective and decreasingly invasive. Thus, the combination of bioelectronic medicine and eNSCs has substantial potential for the treatment of NDs.

Collagen code in tumor microenvironment: Functions, molecular mechanisms, and therapeutic implications.

The tumor microenvironment (TME) is crucial in cancer progression, and the extracellular matrix (ECM) is an important TME component. Collagen is a major ECM component that contributes to tumor cell infiltration, expansion, and distant metastasis during cancer progression. Recent studies reported that collagen is deposited in the TME to form a collagen wall along which tumor cells can infiltrate and prevent drugs from working on the tumor cells. Collagen-tumor cell interaction is complex and requires the activation of multiple signaling pathways for biochemical and mechanical signaling interventions. In this review, we examine the effect of collagen deposition in the TME on tumor progression and discuss the interaction between collagen and tumor cells. This review aims to illustrate the functions and mechanisms of collagen in tumor progression in the TME and its role in tumor therapy. The findings indicated collagen in the TME appears to be a better target for cancer therapy.

CircCPSF6 promotes hepatocellular carcinoma cancer progression by regulating MAP4K4 through sponging miR-145-5p.

BACKGROUND: Aberrant expression of circRNAs is involved in the progression of hepatocellular carcinoma (HCC). This study aimed at screening the pro-tumorigenic circular RNAs (circRNAs) in HCC and the mechanisms of circCPSF6 expression influencing HCC characteristics. METHOD: circCPSF6 was identified in HCC tissues using high-throughput sequencing data, and its expression was verified in both HCC tissues and cell lines using quantitative real-time PCR (qRT-PCR). CCK-8 and Transwell assays were used to evaluate the effects of circCPSF6 on HCC proliferation and migration. A xenograft mouse model was used to investigate the effects of circCPSF6 on HCC progression in vivo, and the significance of circCPSF6 in HCC was verified both in vivo and in vitro. circCPSF6-associated miRNAs and mRNAs were identified using bioinformatic analyses. Luciferase reporter, RNA pull-down, Fluorescence in situ hybridization, and RNA immunoprecipitation assays were performed to elucidate the circCPSF6 regulatory axis in HCC. RESULT: CircCPSF6 expression was increased in HCC cell lines and tissues, and the expression of its parental mRNA was positively correlated with tumor severity and negatively correlated with survival. Mechanistic analyses of HCC cell lines showed that tumorigenesis was inhibited by circCPSF6 knockdown and promoted by its overexpression. Functional analyses revealed that circCPSF6 mediated HCC development by sponging miR-145-5p as a competing endogenous RNA. Furthermore, this sponging upregulated the miR-145-5p target gene MAP4K4, a classical pro-tumorigenic gene. CONCLUSION: Our findings reveal a regulatory network that includes the circCPSF6-miR-145-5p-MAP4K4 axis. Elements of this axis are potential HCC biomarkers, as well as targets for HCC treatment.

Adipocyte-derived extracellular vesicles: bridging the communications between obesity and tumor microenvironment.

By the year 2035 more than 4 billion people might be affected by obesity and being overweight. Adipocyte-derived Extracellular Vesicles (ADEVs/ADEV-singular) are essential for communication between the tumor microenvironment (TME) and obesity, emerging as a prominent mechanism of tumor progression. Adipose tissue (AT) becomes hypertrophic and hyperplastic in an obese state resulting in insulin resistance in the body. This modifies the energy supply to tumor cells and simultaneously stimulates the production of pro-inflammatory adipokines. In addition, obese AT has a dysregulated cargo content of discharged ADEVs, leading to elevated amounts of pro-inflammatory proteins, fatty acids, and carcinogenic microRNAs. ADEVs are strongly associated with hallmarks of cancer (proliferation and resistance to cell death, angiogenesis, invasion, metastasis, immunological response) and may be useful as biomarkers and antitumor therapy strategy. Given the present developments in obesity and cancer-related research, we conclude by outlining significant challenges and significant advances that must be addressed expeditiously to promote ADEVs research and clinical applications.

A gluten degrading probiotic Bacillus subtilis LZU-GM relieve adverse effect of gluten additive food and balances gut microbiota in mice.

Gluten accumulation damages the proximal small intestine and causes celiac disease (CeD) which has not been effectively treated except by using a gluten-free diet. In this study, strain Bacillus subtilis LZU-GM was isolated from Pakistani traditional fermented sourdough and could degrade 73.7% of gluten in 24 h in vitro. Strain LZU-GM was employed for practical application to investigate gluten degradation in mice models. The results showed that strain LZU-GM was colonized in mice and the survival rate was around 0.95 % (P < 0.0001). The gluten degradation was 3-fold higher in the small intestine of the strain LZU-GM treated mice group remaining 1511.96 ng/mL of gluten peptides than the untreated mice group (6500.38 ng/mL). Immunochemical analysis showed that gluten-treated mice established positive antigliadin antibodies (AGA) in serum (IgA, IgG, and anti-TG2 antibodies) as compared to the strain LZU-GM treatment group. Furthermore, the number of IFN-γ, TNF-α, IL-10, and COX-2 cells decrease in the lamina propria of the strain LZU-GM treatment group (P < 0.0001). Microbial community bar plot analysis showed that Lactobacillus, Dubosiella, and Enterococcus genera were restored and stabilized in the LZU-GM treatment group while Blautia and Ruminococcus were found lower. The oral gavage of probiotic strain LZU-GM might be useful for gluten metabolism in the intestine during digestion and would be a long-term dietary treatment for CeD management.

Spatial epigenome-transcriptome comapping technology.

Spatial omics facilitate an in-depth understanding of cell states and cell interactions. Recent work by Zhang et al. simultaneously seizes spatial epigenetic priming, differentiation, and gene regulation at nearly single-cell resolution by developing an epigenome-transcriptome comapping technology. This work displays how epigenetic features influence cell dynamics and transcriptional phenotypes at spatial and genome-wide levels.

CBL0137 activates ROS/BAX signaling to promote caspase-3/GSDME-dependent pyroptosis in ovarian cancer cells.

Curaxin CBL0137 was designed to regulate p53 and nuclear factor-κB simultaneously and exhibits antitumor activity by inhibiting tumor cell proliferation and inducing apoptosis in multiple cancers. However, whether CBL0137 can induce pyroptosis has not yet been reported. This study demonstrated that CBL0137 induces caspase-3/gasdermin E (GSDME)-dependent pyroptosis via the reactive oxygen species (ROS)/BAX pathway. In ovarian cancer cells, CBL0137 inactivated the chromatin remodeling complex which could facilitate chromatin transcription, leading to the decreased transcription of antioxidant genes and oxidation and causing increased ROS levels. BAX was recruited on the mitochondrial membrane by mitochondrial ROS and induced the release of cytochrome c to cleave caspase-3. This led to the cleavage of the N-terminal of GSDME to form pores on the cell membrane and induced pyroptosis. Results of in vivo experiments revealed that CBL0137 also had anti-tumor effects on ovarian cancer cells in vivo. Our study outcomes reveal the mechanisms and targets of CBL0137 inducing pyroptosis in ovarian cancer cells and indicate that CBL0137 is a promising therapeutic agent for ovarian cancer.

Vagus innervation in the gastrointestinal tumor: Current understanding and challenges.

The vagus nerve (VN) is the main parasympathetic nerve of the autonomic nervous system. It is widely distributed in the gastrointestinal tract and maintains gastrointestinal homeostasis with the sympathetic nerve under physiological conditions. The VN communicates with various components of the tumor microenvironment to positively and dynamically affect the progression of gastrointestinal tumors (GITs). The intervention in vagus innervation delays GIT progression. Developments in adeno-associated virus vectors, nanotechnology, and in vivo neurobiological techniques have enabled the creation of precisely regulated "tumor neurotherapies". The present review aimed to summarize the mechanisms of communication between the VN and the gastrointestinal TME and to explore the potential and challenges of VN-based tumor neurotherapy in GITs.

Neuroprotective and anti-epileptic potentials of genus Artemisia L.

The Genus Artemisia L. is one of the largest genera in the Asteraceae family growing wild over in Europe, North America, and Central Asia and has been widely used in folk medicine for the treatment of various ailments. Phytochemical and psychopharmacological studies indicated that the genus Artemisia extracts contain various antioxidant and anti-inflammatory compounds and possess antioxidant, anti-inflammatory, antimicrobial, antimalarial, and antitumor activity. Recently, increasing experimental studies demonstrated that many Artemisia extracts offer a great antiepileptic potential, which was attributed to their bioactive components via various mechanisms of action. However, detailed literature on the antiepileptic properties of the genus Artemisia and its mechanism of action is segregated. In this review, we tried to gather the detailed neuroprotective and antiepileptic properties of the genus Artemisia and its possible underlying mechanisms. In this respect, 63 articles were identified in the PubMed and Google scholars databases, from which 18 studies were examined based on the pharmacological use of the genus Artemisia species in epilepsy. The genus Artemisia extracts have been reported to possess antioxidant, anti-inflammatory, neurotransmitter-modulating, anti-apoptotic, anticonvulsant, and pro-cognitive properties by modulating oxidative stress caused by mitochondrial ROS production and an imbalance of antioxidant enzymes, by protecting mitochondrial membrane potential required for ATP production, by upregulating GABA-A receptor and nACh receptor activities, and by interfering with various anti-inflammatory and anti-apoptotic signaling pathways, such as mitochondrial apoptosis pathway, ERK/CREB/Bcl-2 pathway and Nrf2 pathway. This review provides detailed information about some species of the genus Artemisia as potential antiepileptic agents. Hence, we recommend further investigations on the purification and identification of the most biological effective compounds of Artemisia and the mechanisms of their action to cure epilepsy and other neurological diseases.

Targeting cancer cachexia: Molecular mechanisms and clinical study.

Cancer cachexia is a complex systemic catabolism syndrome characterized by muscle wasting. It affects multiple distant organs and their crosstalk with cancer constitute cancer cachexia environment. During the occurrence and progression of cancer cachexia, interactions of aberrant organs with cancer cells or other organs in a cancer cachexia environment initiate a cascade of stress reactions and destroy multiple organs including the liver, heart, pancreas, intestine, brain, bone, and spleen in metabolism, neural, and immune homeostasis. The role of involved organs turned from inhibiting tumor growth into promoting cancer cachexia in cancer progression. In this review, we depicted the complicated relationship of cancer cachexia with the metabolism, neural, and immune homeostasis imbalance in multiple organs in a cancer cachexia environment and summarized the treatment progress in recent years. And we discussed the molecular mechanism and clinical study of cancer cachexia from the perspective of multiple organs metabolic, neurological, and immunological abnormalities. Updated understanding of cancer cachexia might facilitate the exploration of biomarkers and novel therapeutic targets of cancer cachexia.

Intercellular communication in the tumour microecosystem: Mediators and therapeutic approaches for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), one of the most common tumours worldwide, is one of the main causes of mortality in cancer patients. There are still numerous problems hindering its early diagnosis, which lead to late patients receiving treatment, and these problems need to be solved urgently. The tumour microecosystem is a complex network system comprising seven parts: the hypoxia niche, immune microenvironment, metabolic microenvironment, acidic niche, innervated niche, mechanical microenvironment, and microbial microenvironment. Intercellular communication is divided into direct contact and indirect communication. Direct contact communication includes gap junctions, tunneling nanotubes, and receptor-ligand interactions, whereas indirect communication includes exosomes, apoptotic vesicles, and soluble factors. Mechanical communication and cytoplasmic exchange are further means of intercellular communication. Intercellular communication mediates the crosstalk between the tumour microecosystem and the host as well as that between cells and cell-free components in the tumour microecosystem, causing changes in the tumour hallmarks of the HCC microecosystem such as changes in tumour proliferation, invasion, apoptosis, angiogenesis, metastasis, inflammatory response, gene mutation, immune escape, metabolic reprogramming, and therapeutic resistance. Here, we review the role of the above-mentioned intercellular communication in the HCC microecosystem and discuss the advantages of targeted intercellular communication in the clinical diagnosis and treatment of HCC. Finally, the current problems and prospects are discussed.

Mesenchymal stem cells-based therapy in liver diseases.

Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.

Reclassification of Hepatocellular Cancer With Neural-Related Genes.

Neural infiltration is a critical component of the tumor microenvironment; however, owing to technological limitations, its role in hepatocellular cancer remains obscure. Herein, we obtained the RNA-sequencing data of liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas database and performed a series of bioinformatic analyses, including prognosis analysis, pathway enrichment, and immune analysis, using the R software packages, Consensus Cluster Plus and Limma. LIHC could be divided into two subtypes according to the expression of neural-related genes (NRGs); moreover, there are statistic differences in the prognosis, stage, and immune regulation between the two subtypes. The prognostic model showed that high expression of NRGs correlated with a poor survival prognosis (P<0.05). Further, CHRNE, GFRA2, GFRA3, and GRIN2D was significantly correlated with LIHC clinical prognosis, clinical stage, immune infiltration, immune response, and vital signaling pathways. There was nerve-cancer crosstalk in LIHC. A reclassification of LIHC based on NRG expression may prove beneficial to clinical practice. CHRNE, GFRA2, GFRA3, and GRIN2D may serve as potential biomarker for liver cancer prognosis or immune response.

Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment.

Based on the enhanced knowledge on the tumor microenvironment (TME), a more comprehensive treatment landscape for targeting the TME has emerged. This microenvironment provides multiple therapeutic targets due to its diverse characteristics, leading to numerous TME-targeted strategies. With multifaced activities targeting tumors and the TME, vitamin C is renown as a promising candidate for combination therapy. In this review, we present new advances in how vitamin C reshapes the TME in the immune, hypoxic, metabolic, acidic, neurological, mechanical, and microbial dimensions. These findings will open new possibilities for multiple therapeutic avenues in the fight against cancer. We also review the available preclinical and clinical evidence of vitamin C combined with established therapies, highlighting vitamin C as an adjuvant that can be exploited for novel therapeutics. Finally, we discuss unresolved questions and directions that merit further investigation.