Biochemistry and Biophysics Reports最新文献

The three-dimensional (3D) kidney organoid is a breakthrough model for recapitulating renal morphology and function in vitro, which is grown from stem cells and resembles mammalian kidney organogenesis. Currently, protocols for cultivating this model from induced pluripotent stem cells (iPSCs) and patient-derived adult stem cells (ASCs) have been widely reported. In recent years, scientists have focused on combining cutting-edge bioengineering and bioinformatics technologies to improve the developmental accuracy of kidney organoids and achieve high-throughput experimentation. As a remarkable tool for mechanistic research of the renal system, kidney organoid has both potential and challenges. In this review, we have described the evolution of kidney organoid establishment methods and highlighted the latest progress leading to a more sophisticated kidney transformation research model. Finally, we have summarized the main applications of renal organoids in exploring kidney disease.

Chimeric antigen receptor (CAR)-modified macrophages are a promising treatment for solid tumor. So far the potential effects of CAR-M cell therapy have rarely been investigated in hepatocellular carcinoma (HCC). Glypican-3 (GPC3) is a biomarker for a variety of malignancies, including liver cancer, which is not expressed in most adult tissues. Thus, it is an ideal target for the treatment of HCC. In this study, we engineered mouse macrophage cells with CAR targeting GPC3 and explored its therapeutic potential in HCC. First, we generated a chimeric adenoviral vector (Ad5f35) delivering an anti-GPC3 CAR, Ad5f35-anti-GPC3-CAR, which using the CAR construct containing the scFv targeting GPC3 and CD3ζ intracellular domain. Phagocytosis and killing effect indicated that macrophages transduced with Ad5f35-anti-GPC3-CAR (GPC3 CAR-Ms) exhibited antigen-specific phagocytosis and tumor cell clearance in vitro, and GPC3 CAR-Ms showed significant tumor-killing effects and promoted expression of pro-inflammatory (M1) cytokines and chemokines. In 3D NACs-origami spheroid model of HCC, CAR-Ms were further demonstrated to have a significant tumor killing effect. Together, our study provides a new strategy for the treatment of HCC through CAR-M cells targeting GPC3, which provides a basis for the research and treatment of hepatocellular carcinoma.

The estrogen-synthesizing enzyme aromatase is expressed in adipose tissue where it controls the local concentration of estrogen. It has been suggested that the organic solvents ethanol and ethylene glycol can induce estrogen synthesis by inhibiting PPARγ activity. Since elevated estrogen synthesis in adipose tissue is a risk factor for breast cancer development, it is of interest to further characterize the mechanisms regulating aromatase expression. Here, we explored the mechanisms by which ethanol and ethylene glycol modulate aromatase mRNA expression and the ultimate conversion of androgens into estrogens.

NMR spectroscopy revealed that ethanol and ethylene glycol influence the active state of PPARγ. An inhibitory effect on PPARγ was confirmed by adipogenesis assays and PPARγ target gene expression analysis in adipocytes. However, only ethanol increased aromatase mRNA in differentiated human adipocytes. In contrast, ethylene glycol downregulated aromatase in a PPARγ-independent manner. An animal study using female Wistar rats was conducted to assess the acute effects of ethanol and ethylene glycol on aromatase expression in adipose tissue within a physiological context. No changes in aromatase or PPARγ target gene (Adipoq and Fabp4) levels were observed in adipose tissue or ovary in response to the chemical exposures, suggesting an absence of acute PPARγ-mediated effects in these organs.

The results suggest that ethanol and ethylene glycol are weak PPARγ antagonists in mouse and human adipocytes as well as in cell-free NMR spectroscopy. Both compounds seem to affect adipocyte aromatase expression in vitro, where ethanol increased aromatase expression PPARγ-dependently and ethylene glycol decreased aromatase expression independently of PPARγ. No acute effects on aromatase expression or PPARγ activity were observed in adipose tissue or ovary in rats in this study design.

Aortic aneurysm and dissection (AAD) are severe vascular diseases with high mortality rates. However, the causal relationship between serum uric acid levels and the occurrence of AAD remains a subject of controversy. To address this issue, we conducted a two-sample Mendelian randomization (MR) analysis to investigate whether there is a causal association between these factors. We obtained single-nucleotide polymorphisms (SNPs) data related to serum uric acid levels from the FinnGen study and data on AAD from the UK Biobank. Various two-sample MR methods, including inverse variance weighted (IVW) analysis, MR-Egger regression analysis, weighted median analysis, and contamination mixture method, were employed to assess the causal relationship between serum uric acid and the risk of AAD. Sensitivity analysis was conducted to evaluate the stability and reliability of the results. The findings revealed a positive association between serum uric acid levels and the risk of aortic aneurysm (AA) (odds ratio [OR] = 1.200, 95 % confidence interval [CI]: 1.020–1.400, P = 0.0239). However, no significant correlation was observed between serum uric acid levels and the occurrence of aortic dissection (AD) (OR = 0.893, 95 % CI = 0.602–1.326, P = 0.576). Our study, which employed MR analysis, identified a positive association between serum uric acid levels and the risk of AA. However, we did not observe a significant correlation with AD.

Background

Umbilical cord blood hematopoietic stem cells (UCB–HSCs) have important roles in the treatment of illnesses based on their self-renewal and potency characteristics. Knowing the gene profiles and signaling pathways involved in each step of the cell cycle could improve the therapeutic approaches of HSCs. The aim of this study was to predict the gene profiles and signaling pathways involved in the G0, G1, and differentiation stages of HSCs.

Methods

Interventional (n = 8) and non-interventional (n = 3) datasets were obtained from the Gene Expression Omnibus (GEO) database, and were crossed and analyzed to determine the high- and low-express genes related to each of the G0, G1, and differentiation stages of HSCs. Then, the scores of STRING were annotated to the gene data. The gene networks were constructed using Cytoscape software, and enriched with the KEGG and GO databases.

Results

The high- and low-express genes were determined due to inter and intra intersections of the interventional and non-interventional data. The non-interventional data were applied to construct the gene networks (n = 6) with the nodes improved using the interventional data. Several important signaling pathways were suggested in each of the G0, G1, and differentiation stages.

Conclusion

The data revealed that the different signaling pathways are activated in each of the G0, G1, and differentiation stages so that their genes may be targeted to improve the HSC therapy.

Cancer is the major cause of premature death in humans worldwide, demanding more efficient therapeutics. Aberrant cell proliferation resulting from the loss of cell cycle regulation is the major hallmark of cancer, so targeting cell cycle is a promising strategy to combat cancer. However, the molecular mechanism underlying the dysregulation of cell cycle of cancer cells remains poorly understood. TMEM189, a newly identified protein, plays roles in the biosynthesis of ethanolamine plasmalogen and the regulation of autophagy. Here, we demonstrated that the expression level of TMEM189 was negatively correlated with the survival rate of the cancer patients. TMEM189 deficiency significantly suppresses the cancer cell proliferation and migration, and causes cell cycle G2/M arrest both in vitro and in vivo. Furthermore, TMEM189 depletion suppressed the growth of breast tumors in vivo. Taken together, our work indicated that TMEM189 promotes cancer progression by regulating cell cycle G2/M transition, suggesting that it is a promising target in cancer therapy.

Lung cancer is a leading cause of cancer-related death, and the most common type of lung cancer is non-small cell lung cancer, which accounts for approximately 85 % of lung cancer diagnoses. Recent studies have revealed that ubiquitination acts as a crucial part of the development and progression of lung cancer. The E1-E2-E3 three-enzyme cascade has a core function in ubiquitination, so targeted adjustments of E3 ligases could be used in lung cancer treatment. Hence, we elucidate research advances in lung cancer-related E3 ligases by briefly describing the structure and categorization of E3 ligases. Here, we provide a detailed review of the mechanisms by which lung cancer-related E3 ligases modify substrate proteins and regulate signaling pathways to facilitate or suppress cancer progression. We hope to show a new perspective on targeted precision therapy for lung cancer.

The renin–angiotensin system (RAS) is best known for playing a major role in maintaining the physiology of the cardiovascular system. Dysregulation of the RAS pathway has been proposed as a link to some malignancies and contributes to cancer metastasis.

Breast cancer is considered as one of the leading causes of cancer death in women and its prevention remains yet a challenge. Elements of RAS are expressed in both normal breast tissue and cancerous cells, signifying the essential role of RAS in breast cancer pathology. Sertraline, a widely used antidepressant, has shown anti-proliferative properties on a variety of malignancies.

This study aimed to investigate the effect of sertraline and its combination with agonists and antagonists of RAS (A779, Ang 1–7 and losartan) on viability of MCF-7 cells along with their effect on apoptosis and distribution of cell cycle. Our results indicated that sertraline, losartan and Ang 1–7 significantly decreased cell viability, induced apoptosis and cell cycle arrest. A779 blunted the effect of sertraline on cell viability, ROS generation and cell cycle arrest. Combination treatment of sertraline with losartan as well as Ang 1–7 caused a remarkable decline in cell viability.

In conclusion, results of the present study support the anti-cancer properties of sertraline, losartan and Ang 1–7 via induction of apoptosis and cell cycle arrest.

Background

Radiotherapy is one of the primary treatments for cancer, but it can cause damage to normal tissues and lead to side effects. The use of radiosensitizers can enhance the sensitivity of cancer cells to radiation, thereby reducing the amount of radiation required and minimizing damage to healthy tissues. Bismuth selenide nanoparticles (Bi2Se3 NPs) have been shown to have potential as radiosensitizers.

Materials and methods

In this study, we investigated the potential of Bi2Se3 NPs as a radiosensitizer in colon cancer cells (HCT-116) in vitro. The cells were treated with various concentrations of Bi2Se3 NPs and then exposed to ionizing radiation. The viability of the cells was assessed using the MTT assay, and the survival rate was evaluated.

Results

Our results showed that Bi2Se3 NPs significantly enhanced the sensitivity of colon cancer cells to ionizing radiation in a dose-dependent manner. The combination of Bi2Se3 NPs and radiation resulted in a significant decrease in cell viability and survival rate compared to radiation alone.

Conclusion

Bi2Se3 NPs have the potential to be used as a radiosensitizer in the treatment of colon cancer. The findings of this study suggest that combining Bi2Se3 NPs with radiation may enhance the effectiveness of radiotherapy and reduce the mortality rate associated with colon cancer. Further studies are needed to investigate the safety and efficacy of this approach in vivo.

RUNX2 is a transcription factor crucial for bone formation. Mutant mice with varying levels of Runx2 expression display dosage-dependent skeletal abnormalities, underscoring the importance of Runx2 dosage control in skeletal formation. RUNX2 activity is regulated by several molecular mechanisms, including epigenetic modification such as DNA methylation. In this study, we investigated whether targeted repressive epigenome editing including hypermethylation to the Runx2-DMR/CpG island shore could influence Runx2 expression using Cas9-based epigenome-editing tools. Through the transient introduction of CRISPRoff-v2.1 and gRNAs targeting Runx2-DMR into MC3T3-E1 cells, we successfully induced hypermethylation of the region and concurrently reduced Runx2 expression during osteoblast differentiation. Although the epigenome editing of Runx2-DMR did not impact the expression of RUNX2 downstream target genes, these results indicate a causal relationship between the epigenetic status of the Runx2-DMR and Runx2 transcription. Additionally, we observed that hypermethylation of the Runx2-DMR persisted for at least 24 days under growth conditions but decreased during osteogenic differentiation, highlighting an endogenous DNA demethylation activity targeting the Runx2-DMR during the differentiation process. In summary, our study underscore the usefulness of the epigenome editing technology to evaluate the function of endogenous genetic elements and revealed that the Runx2-DMR methylation is actively regulated during osteoblast differentiation, subsequently could influence Runx2 expression.