Lomitapide repurposing for treatment of malignancies: A promising direction.

The development of novel drugs from basic science to clinical practice requires several years, much effort, and cost. Drug repurposing can promote the utilization of clinical drugs in cancer therapy. Recent studies have shown the potential effects of lomitapide on treating malignancies, which is currently used for the treatment of familial hypercholesterolemia. We systematically review possible functions and mechanisms of lomitapide as an anti-tumor compound, regarding the aspects of apoptosis, autophagy, and metabolism of tumor cells, to support repurposing lomitapide for the clinical treatment of tumors.

The symbiont Wolbachia alleviates pesticide susceptibility in the two-spotted spider mite Tetranychus urticae through enhanced host detoxification pathways.

The two-spotted spider mite (Tetranychus urticae) is one of the most well-known pesticide-resistant agricultural pests, with resistance often attributed to changes such as target-site mutations and detoxification activation. Recent studies show that pesticide resistance can also be influenced by symbionts, but their involvement in this process in spider mites remains uncertain. Here, we found that infection with Wolbachia, a well-known bacterial reproductive manipulator, significantly increased mite survival after exposure to the insecticides abamectin, cyflumetofen, and pyridaben. Wolbachia-infected (WI) mites showed higher expression of detoxification genes such as P450, glutathione-S-transferase (GST), ABC transporters, and carboxyl/cholinesterases. RNA interference experiments confirmed the role of the two above-mentioned detoxification genes, TuCYP392D2 and TuGSTd05, in pesticide resistance. Increased GST activities were also observed in abamectin-treated WI mites. In addition, when wild populations were treated with abamectin, WI mites generally showed better survival than uninfected mites. However, genetically homogeneous mites with different Wolbachia strains showed similar survival. Finally, abamectin treatment increased Wolbachia abundance without altering the mite's bacterial community. This finding highlights the role of Wolbachia in orchestrating pesticide resistance by modulating host detoxification. By unraveling the intricate interplay between symbionts and pesticide resistance, our study lays the groundwork for pioneering strategies to combat agricultural pests.

Application of three-dimensional (3D) bioprinting in anti-cancer therapy.

Three-dimensional (3D) bioprinting is a novel technology that enables the creation of 3D structures with bioinks, the biomaterials containing living cells. 3D bioprinted structures can mimic human tissue at different levels of complexity from cells to organs. Currently, 3D bioprinting is a promising method in regenerative medicine and tissue engineering applications, as well as in anti-cancer therapy research. Cancer, a type of complex and multifaceted disease, presents significant challenges regarding diagnosis, treatment, and drug development. 3D bioprinted models of cancer have been used to investigate the molecular mechanisms of oncogenesis, the development of cancers, and the responses to treatment. Conventional 2D cancer models have limitations in predicting human clinical outcomes and drug responses, while 3D bioprinting offers an innovative technique for creating 3D tissue structures that closely mimic the natural characteristics of cancers in terms of morphology, composition, structure, and function. By precise manipulation of the spatial arrangement of different cell types, extracellular matrix components, and vascular networks, 3D bioprinting facilitates the development of cancer models that are more accurate and representative, emulating intricate interactions between cancer cells and their surrounding microenvironment. Moreover, the technology of 3D bioprinting enables the creation of personalized cancer models using patient-derived cells and biomarkers, thereby advancing the fields of precision medicine and immunotherapy. The integration of 3D cell models with 3D bioprinting technology holds the potential to revolutionize cancer research, offering extensive flexibility, precision, and adaptability in crafting customized 3D structures with desired attributes and functionalities. In conclusion, 3D bioprinting exhibits significant potential in cancer research, providing opportunities for identifying therapeutic targets, reducing reliance on animal experiments, and potentially lowering the overall cost of cancer treatment. Further investigation and development are necessary to address challenges such as cell viability, printing resolution, material characteristics, and cost-effectiveness. With ongoing progress, 3D bioprinting can significantly impact the field of cancer research and improve patient outcomes.

SIX4, a potential therapeutic target for estrogen receptor-positive breast cancer patients, is associated with low promoter methylation level.

Aim: To investigate SIX4 in breast cancer. Methods: Publicly available online tools were used to analyze the expression, methylation and prognostic significance of SIX4 in breast cancer, as well as its immunohistochemistry. Results: High SIX4 levels were associated with low SIX4 promoter methylation, especially in estrogen receptor-positive breast cancer. Increased SIX4 was related to advanced stage and decreased immune infiltration. Gene set enrichment analysis found that the SIX4-correlated genes were enriched in transcriptional processing and immune response. Patients with high SIX4 expression tended to have poor survival, especially those with estrogen receptor-positive breast cancer. Conclusion: High SIX4 expression in breast cancer plays an oncogenic role, promoting the development of malignancies through suppressing the immune response, especially in luminal subtypes, and is associated with a low promoter methylation level.

Immune responses of six-transmembrane epithelial antigen of the prostate 4 functions as a novel biomarker in gastric cancer.

BACKGROUND: Immune cells play an important role in regulating the behavior of tumor cells. According to emerging evidence, six-transmembrane epithelial antigen of the prostate 4 (STEAP4) performs a crucial part in tumor microenvironmental immune response and tumorigenesis, and serves as the potential target for cellular and antibody immunotherapy. However, the immunotherapeutic role of STEAP4 in gastric cancer (GC) remains unclear. AIM: To investigate the expression of STEAP4 in GC and its relationship with immune infiltrating cells, and explore the potential value of STEAP4 as an immune prognostic indicator in GC. METHODS: The expression level of STEAP4 was characterized by immunohistochemistry in tumors and adjacent non-cancerous samples in 96 GC patients. Tumor Immune Estimation Resource was used to study the correlation between STEAP4 and tumor immune infiltration level and immune infiltration gene signature. R package was used to analyze the relationship between STEAP4 expression and immune and stromal scores in GC (GSE62254) by the ESTIMATE algorithm, and Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis were applied to analyze the effect of STEAP4 on clinical prognosis. RESULTS: Immunohistochemistry analysis showed that STEAP4 expression was higher in GC tissues than in adjacent tissues, and STEAP4 expression was positively correlated with the clinical stage of GC. In GC, the expression of STEAP4 was positively correlated with the infiltration levels of B cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. The expression level of STEAP4 was strongly correlated with most of the immune markers. In addition, STEAP4 expression was inversely correlated with tumor purity, but correlated with stromal score (r = 0.43, P < 0.001), immune score (r = 0.29, P < 0.001) and estimate score (r = 0.39, P < 0.001). Moreover, stromal, immune, and estimate scores were higher in the STEAP4 high expression group, whereas tumor purity was higher in the STEAP4 Low expression group. The relationship between STEAP4 expression and prognosis of patients with GC was further investigated, and the results showed that high STEAP4 expression was associated with poor overall survival and disease-free survival. In addition, Kaplan-Meier Plotter showed that high expression of STEAP4 was significantly correlated with poor survival of patients with GC. CONCLUSION: The current findings suggest an oncogenic role for STEAP4 in GC, with significantly high levels being associated with poor prognosis. Investigation of the GC tumor microenvironment suggests the potential function of STEAP4 is connected with the infiltration of diverse immune cells, which may contribute to the regulation of the tumor microenvironment. In conclusion, STEAP4 may serve as a potential therapeutic target for GC to improve the immune infiltration, as well as serve as a prognostic biomarker for judging the prognosis and immune infiltration status of GC.

Exosomes in metastasis of colorectal cancers: Friends or foes?

Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.

Compositional and functional aberrance of the gut microbiota in treatment-naïve patients with primary Sjögren's syndrome.

OBJECTIVES: To investigate the compositional and functional characteristics of the gut microbiota in primary Sjögren's syndrome (pSS) and compare them with those in systemic lupus erythematosus (SLE). METHODS: Stool samples from 78 treatment-naïve pSS patients and 78 matched healthy controls were detected by shotgun metagenomic sequencing and compared with those from 49 treatment-naïve SLE patients. The virulence loads and mimotopes of the gut microbiota were also assessed by sequence alignment. RESULTS: The gut microbiota of treatment-naïve pSS patients had lower richness and evenness and showed a different community distribution than that of healthy controls. The microbial species enriched in the pSS-associated gut microbiota included Lactobacillus salivarius, Bacteroides fragilis, Ruminococcus gnavus, Clostridium bartlettii, Clostridium bolteae, Veillonella parvula, and Streptococcus parasanguinis. Lactobacillus salivarius was the most discriminating species in the pSS patients, especially in those with interstitial lung disease (ILD). Among the differentiating microbial pathways, the superpathway of l-phenylalanine biosynthesis was also further enriched in pSS complicated with ILD. There were more virulence genes carried by the gut microbiota in pSS patients, most of which encoded peritrichous flagella, fimbriae, or curli fimbriae, three types of bacterial surface organelles involved in bacterial colonization and invasion. Five microbial peptides with the potential to mimic pSS-related autoepitopes were also enriched in the pSS gut. SLE and pSS shared significant gut microbial traits, including community distribution, altered microbial taxonomy and pathways, and enriched virulence genes. However, Ruminococcus torques was depleted in pSS patients but enriched in SLE patients compared to healthy controls. CONCLUSIONS: The gut microbiota in treatment-naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.

Review of ferroptosis in colorectal cancer: Friends or foes?

Ferroptosis is a newly discovered type of cell-regulated death. It is characterized by the accumulation of iron-dependent lipid peroxidation and can be distinguished from other forms of cell-regulated death by different morphology, biochemistry, and genetics. Recently, studies have shown that ferroptosis is associated with a variety of diseases, including liver, kidney and neurological diseases, as well as cancer. Ferroptosis has been shown to be associated with colorectal epithelial disorders, which can lead to cancerous changes in the gut. However, the potential role of ferroptosis in the occurrence and development of colorectal cancer (CRC) is still controversial. To elucidate the underlying mechanisms of ferroptosis in CRC, this article systematically reviews ferroptosis, and its cellular functions in CRC, for furthering the understanding of the pathogenesis of CRC to aid clinical treatment.

Compositional and functional aberrance of the gut microbiota in treatment naïve patients with primary Sjögren's syndrome.

OBJECTIVES: To investigate the compositional and functional characteristics of the gut microbiota in primary Sjögren's syndrome (pSS) and compare them with those in systemic lupus erythematosus (SLE). METHODS: Stool samples from 78 treatment naïve pSS patients and 78 matched healthy controls were detected by shotgun metagenomic sequencing and compared with those from 49 treatment naïve SLE patients. The virulence loads and mimotopes of the gut microbiota were also assessed by sequence alignment. RESULTS: The gut microbiota of treatment naïve pSS patients had lower richness and evenness and showed a different community distribution than that of healthy controls. The microbial species enriched in the pSS-associated gut microbiota included Lactobacillus salivarius, Bacteroides fragilis, Ruminococcus gnavus, Clostridium bartlettii, Clostridium bolteae, Veillonella parvula, and Streptococcus parasanguinis. Lactobacillus salivarius was the most discriminating species in the pSS patients, especially in those with interstitial lung disease (ILD). Among the differentiating microbial pathways, the superpathway of l-phenylalanine biosynthesis was also further enriched in pSS complicated with ILD. There were more virulence genes carried by the gut microbiota in pSS patients, most of which encoded peritrichous flagella, fimbriae, or curli fimbriae, three types of bacterial surface organelles involved in bacterial colonization and invasion. Five microbial peptides with the potential to mimic pSS-related autoepitopes were also enriched in the pSS gut. SLE and pSS shared significant gut microbial traits, including the community distribution, altered microbial taxonomy and pathways, and enriched virulence genes. However, Ruminococcus torques was depleted in pSS patients but enriched in SLE patients compared to that in healthy controls. CONCLUSIONS: The gut microbiota in treatment naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.

An Autoimmunogenic and Proinflammatory Profile Defined by the Gut Microbiota of Patients With Untreated Systemic Lupus Erythematosus.

OBJECTIVE: Changes in gut microbiota have been linked to systemic lupus erythematosus (SLE), but knowledge is limited. Our study aimed to provide an in-depth understanding of the contribution of gut microbiota to the immunopathogenesis of SLE. METHODS: Fecal metagenomes from 117 patients with untreated SLE and 52 SLE patients posttreatment were aligned with 115 matched healthy controls and analyzed by whole-genome profiling. For comparison, we assessed the fecal metagenome of MRL/lpr mice. The oral microbiota origin of the gut species that existed in SLE patients was documented by single-nucleotide polymorphism-based strain-level analyses. Functional validation assays were performed to demonstrate the molecular mimicry of newly found microbial peptides. RESULTS: Gut microbiota from individuals with SLE displayed significant differences in microbial composition and function compared to healthy controls. Certain species, including the Clostridium species ATCC BAA-442 as well as Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis, and Clostridium leptum, were enriched in SLE gut microbiota and reduced after treatment. Enhanced lipopolysaccharide biosynthesis aligned with reduced branched chain amino acid biosynthesis was observed in the gut of SLE patients. The findings in mice were consistent with our findings in human subjects. Interestingly, some species with an oral microbiota origin were enriched in the gut of SLE patients. Functional validation assays demonstrated the proinflammatory capacities of some microbial peptides derived from SLE-enriched species. CONCLUSION: This study provides detailed information on the microbiota of untreated patients with SLE, including their functional signatures, similarities with murine counterparts, oral origin, and the definition of autoantigen-mimicking peptides. Our data demonstrate that microbiome-altering approaches may offer valuable adjuvant therapies in SLE.