Targeting HIF-1α with Specific DNA Yokes for Effective Anticancer Therapy.

Hypoxia, a ubiquitous hallmark in cancer, underscores the significance of targeting HIF-1α, the principal transcriptional factor of hypoxic responses, for effective cancer therapy. Herein, DNA yokes, a novel class of DNA nanomaterials harboring specific HIF-1α binding sequences (hypoxia response elements, HREs), are introduced as nanopharmaceuticals for cancer treatment. Comprising a basal tetrahedral DNA nanostructure and four HRE-bearing overhanging chains, DNA yokes exhibit exceptional stability and prolonged intracellular retention. The investigation reveals their capacity to bind HIF-1α, thereby disrupting its interaction with the downstream genomic DNAs and impeding transcriptional activity. Moreover, DNA yokes facilitate HIF-1α degradation via the ubiquitination pathway, thereby sequestering it from downstream targets and ultimately promoting its degradation. In addition, DNA yokes attenuate cancer cell proliferation, migration, and invasion under hypoxic conditions, while also displaying preferential accumulation within tumors, thereby inhibiting tumor growth and metastasis in vivo. This study pioneers a novel approach to cancer therapy through the development of DNA-based drugs characterized by high stability and low toxicity to normal cells, positioning DNA yokes as promising candidates for cancer treatment.

The varying clinical effectiveness of single, three and five intraarticular injections of platelet-rich plasma in knee osteoarthritis.

OBJECTIVE: To investigate the variations in clinical effectiveness among patients diagnosed with knee osteoarthritis who underwent intra-articular administration of platelet-rich plasma using single, triple, or quintuple injections. METHODS: One hundred twenty patients with grade I-III knee osteoarthritis were randomly assigned to three groups: PRP1 group, who received a single injection of platelet-rich plasma; PRP3 group, who received three PRP injections one week apart; PRP5 group, who received five PRP injections one week apart. The patients' conditions were evaluated using the Visual Analogue Scale (VAS) and the Western Ontario and McMaster Universities Arthritis Index-VA3.1 version (WOMAC-VA3.1) at baseline and 6, 12, 24, and 52 weeks 52 weeks follow up. RESULTS: Out of the total participants, 106 patients (30 males and 76 females) completed the study. The primary outcome measure, WOMAC pain score, registered significant improvements across all groups when compared to pre-treatment levels. However, the application of 3 and 5 injections of platelet-rich plasma was substantially more effective than that of a single injection in reducing knee pain and stiffness, as well as enhancing physical function in patients with knee osteoarthritis. No statistically discernable difference was observed between PRP3 and PRP5 at all follow-up intervals, and there was no discernable difference between 3 and 5 PRP injections either. Mild side effects occurred in all three groups. CONCLUSIONS: The administration of three or five injections of platelet-rich plasma is safe, substantially more effective than single injections, and leads to remarkable clinical improvement by significantly reducing knee pain, improving joint stiffness, and enhancing physical function in patients with grade I-III knee osteoarthritis. Furthermore, no significant difference was observed in the efficacy of three or five injections. Therefore, we recommend using three injections of PRP in the treatment of patients with knee osteoarthritis of grade I-III.

Tumor suppressor function of RBMS3 overexpression in EOC associated with immune cell infiltration.

Objectives: Epithelial ovarian cancer (EOC) is considered to be a prevalent female malignancy with both high incidence and mortality. It is reported that RNA-binding protein 3 (RBMS3) executives a tumor suppressor function in different cancers. This investigation was designed to examine the expression of RBMS3 in epithelial ovarian cancer, the effects on EOC cells, and its connection to immune cells that infiltrate tumors in the EOC microenvironment. Methods: The expression levels of RBMS3 in EOC tissues as well as their correlations with immune cell infiltration and clinical outcome were examined using bioinformatics approaches. Western blotting as well as immunohistochemistry were carried out to determine the protein levels in EOC tissues. In addition, qRT-PCR was employed to look at the expression of the mRNA. The role of RBMS3 in EOC cells was investigated, and an RBMS3 lentiviral vector was developed. The effects of RBMS3 on subcutaneous tumor development, the proliferation protein Ki-67, the tumor angiogenesis indicator CD31, and its function in controlling the tumor immune microenvironment were evaluated by in vivo tests. Results: There was a considerable decrease in RBMS3 expression in EOC tissues, which was linked to a poor prognosis for patients and the infiltration of multiple immune cell. Given immunohistochemical studies, tissues with increased RBMS3 expression had decreased markers of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages, whereas M1 macrophage markers were elevated. RBMS3 appears to suppress the capabilities of proliferating, invading, and migrating in EOC cells according to in vitro tests, whereas tumors overexpressing RBMS3 developed more slowly in syngeneic mouse models. The overexpression of RBMS3 led to a decline in the levels of Ki-67 protein and CD31. Additionally, it showed a negatively correlation with markers of regulatory T cell, myeloid-derived suppressor cell, and M2 macrophage but a positive correlation with markers of M1 macrophage. Conclusions: The findings revealed that elevated RBMS3 expression plays a tumor suppressor role in EOC and was connected to patient survival in EOC. The studies conducted in vitro and in vivo demonstrated a link between RBMS3 expression and the infiltration of certain immune cells, indicating a function for RBMS3 in the immunosuppressive tumor microenvironment and its promising efficiency as a novel target for immunotherapy against EOC.

ACE2: the node connecting the lung cancer and COVID-19.

Angiotensin-converting Enzyme 2 (ACE2) collaborates with Angiotensin (Ang) 1-7 and Mas receptors to establish the ACE2-Ang (1-7)-Mas receptor axis. ACE2 impacts lung function and can cause lung injury due to its inflammatory effects. Additionally, ACE2 contributes to pulmonary vasculature dysfunction, resulting in pulmonary hypertension. In addition, ACE2 is a receptor for coronavirus entry into host cells, leading to coronavirus infection. Lung cancer, one of the most common respiratory diseases worldwide, has a high rate of infection. Elevated levels of ACE2 in lung cancer patients, which increase the risk of SARS-CoV-2 infection and severe disease, have been demonstrated in clinical studies and by molecular mechanisms. The association between lung cancer and SARS-CoV-2 is closely linked to ACE2. This review examines the basic pathophysiological role of ACE2 in the lung, the long-term effects of SARS-CoV-2 infection on lung function, the development of pulmonary fibrosis, chronic inflammation in long-term COVID patients, and the clinical research and mechanisms underlying the increased susceptibility of lung cancer patients to the virus. Possible mechanisms of lung cancer in SARS-CoV-2-infected individuals and the potential role of ACE2 in this process are also explored in this review. The role of ACE2 as a therapeutic target in the novel coronavirus infection process is also summarized. This will help to inform prevention and treatment of long-term pulmonary complications in patients.

Hepatic polypeptide nutrient solution improves high-cholesterol diet-induced rats with nonalcoholic fatty liver disease by activating AMP-activated protein kinase signaling pathway.

Hepatic polypeptide nutrient solution (HP) is a mixture of hepatoprotective peptides derived from fresh porcine liver with various effects. However, the role and mechanisms of HP in nonalcoholic fatty liver disease (NAFLD) are still not well understood. We investigated the effects of HP NAFLD rats induced by high-cholesterol diet (HCD) and its underlying mechanisms. Rats were provided with HCD for 4 weeks and then received HP or metformin after 2 weeks of HCD feeding. The study found that HP reduced cholesterol and triglyceride levels in rats with NAFLD (all p < .05). Histopathological examination also showed that HP improved the liver lesions induced by the HCD diet. Furthermore, the oxidative stress and inflammatory responses of NAFLD rats treated with HP were also improved. In addition, it was discovered that HP triggered the activation of AMPK and decreased the expression of SREBP-1c and FAS while enhancing the expression of PPAR α and CPT-1 in liver. These findings indicated that HP might have therapeutic potential for NAFLD, possibly via activating AMPK signaling pathway.

The coexistence of papillary thyroid carcinoma, anaplastic thyroid carcinoma (squamous cell carcinoma subtype) and poorly differentiated thyroid carcinoma: a case report.

Background: Papillary thyroid carcinoma (PTC) accounts for about 60% of adult thyroid carcinoma and generally has an excellent prognosis. Primary squamous cell carcinoma of thyroid (PSCCT) is a rare thyroid tumor with high malignancy and poor prognosis. In 2022, the 5th edition of World Health Organization (WHO) has classified it as a subtype of anaplastic thyroid carcinoma (ATC), abbreviated as ATC-squamous cell carcinoma (SCC) subtype. Poorly differentiated thyroid carcinoma (PDTC) is a kind of follicular-derived malignancy, which is prone to recurrence and distant metastasis. Here, we report a rare case of the coexistence of PTC, ATC-SCC subtype and PDTC. Case Description: We herein report a case of 69-year-old female who initially presented with a history of left neck mass for one month. Comprehensive auxiliary examinations and postoperative pathology confirmed the diagnosis of PTC combined with ATC-SCC subtype, and PDTC. Total thyroidectomy with radical left cervical lymph node dissection was performed, followed by thyroid-stimulating hormone (TSH) suppressive therapy, 131I, radiotherapy and chemotherapy. The patient showed no tumor recurrence or metastasis after a 5-month postoperative follow-up. Conclusions: The simultaneous occurrence of PTC, ATC-SCC subtype, and PDTC is extremely rare in clinical terms or literature reports. The treatment has not been standardized, and early radical surgery is the first choice. In addition, the combination of adjuvant therapies such as TSH suppressive therapy, radiotherapy, chemotherapy and 131I may further improve the prognosis of the patient.

Self-esteem, depression, anxiety and sexual function in Mayer-Rokitansky-Küster-Hauser syndrome with neovagina: A case series.

BACKGROUND: The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare condition with significant psychological implications. However, our understanding of its impact on postoperative sexual function and mental health is still limited. AIM: Evaluate the mental health status and sexual functioning of women with MRKH syndrome after vaginoplasty surgery. METHODS: We enrolled 53 cases with MRKH syndrome who underwent artificial vaginoplasty. The participants were asked to participate in a two-round survey conducted between February 2021 during the covid-19 period and March 2023. The survey included questionnaires to measure depression, anxiety, self-esteem, and sexual functioning. Differences between scores over time were analysed using a paired sample t-test, and we assessed the correlation between mental health and sexual functioning. RESULTS: In the first round, patients' mean ± SD age at surgery was 23.6 ± 4.5 years old, and the mean ± SD time that had elapsed since surgery at the time of the survey was 34.2 ± 20.8 months. None of the patients reported low self-esteem, 45.3 % reported mild-to-moderate depression, and 34.0 % reported mild anxiety. Thirty patients have had vaginal intercourse during the last six months. The mean ± SD Female Sexual Functioning Index score was 24.6 ± 4.4, and 60.0 % had a score of 23.5 or higher, indicating high sexual functioning. The sexual functioning scores were positively correlated with self-esteem scores and negatively correlated with depression or anxiety scores (p < 0.05). There was no significant improvement in patient's mental health status and sexual function between the second round survey (71.3 ± 17.8 months after surgery) and the first round survey (p > 0.05). In contrast, the sexual arousal of FSFI were significantly higher in the second survey round (p < 0.05). CONCLUSION: Most patients undergoing vaginoplasty reported persisting mental health challenges. However, the majority reported good sexual functioning.

A Tumor Environment-Activated Photosensitized Biomimetic Nanoplatform for Precise Photodynamic Immunotherapy of Colon Cancer.

Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG2000-SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies.

Functional mouse hepatocytes derived from interspecies chimeric livers effectively mitigate chronic liver fibrosis.

Liver disease is a major global health challenge. There is a shortage of liver donors worldwide, and hepatocyte transplantation (HT) may be an effective treatment to overcome this problem. However, the present approaches for generation of hepatocytes are associated with challenges, and interspecies chimera-derived hepatocytes produced by interspecies blastocyst complementation (IBC) may be promising donor hepatocytes because of their more comprehensive hepatic functions. In this study, we isolated mouse hepatocytes from mouse-rat chimeric livers using IBC and found that interspecies chimera-derived hepatocytes exhibited mature hepatic functions in terms of lipid accumulation, glycogen storage, and urea synthesis. Meanwhile, they were more similar to endogenous hepatocytes than hepatocytes derived in vitro. Interspecies chimera-derived hepatocytes could relieve chronic liver fibrosis and reside in the injured liver after transplantation. Our results suggest that interspecies chimera-derived hepatocytes are a potentially reliable source of hepatocytes and can be applied as a therapeutic approach for HT.

Intraoperative quantitative crystalline lens nuclear opacities analysis based on crystalline lenSx platform.

PURPOSE: The main objective is to quantify the lens nuclear opacity using spectral-domain optical coherence tomography (SD-OCT) and to evaluate its association with Lens Opacities Classification System III (LOCS-III) system, lens thickness (LT), and surgical parameters. The secondary objective is to assess the diagnostic model performance for hard nuclear cataract. METHODS: This study included 70 eyes of 57 adults with cataract, with 49 (70%) and 21 (30%) in training and validation cohort, respectively. Correlations of the average nuclear density (AND) /maximum nuclear density (MND) with LOCS-III scores, LT, and surgical parameters were analyzed. Univariate and multivariate logistic regression analysis, receiver operating characteristic curves and calibration curves were performed for the diagnostic of hard nuclear cataract. RESULTS: The pre-operative uncorrected distance visual acuity (UDVA), intraocular pressure (IOP), mean axial length (AL), and LT were 1.20 ± 0.47 log MAR, 15.50 ± 2.87 mmHg, 27.34 ± 3.77 mm and 4.32 ± 0.45 mm, respectively. The average nuclear opalescence (NO) and nuclear colour (NC) scores were 3.61 ± 0.94 and 3.50 ± 0.91 (ranging from 1.00 to 6.90), respectively. The average AND and MND were 137.94 ± 17.01 and 230.01 ± 8.91, respectively. NC and NO scores both significantly correlated with the AND (rNC = 0.733, p = 0.000; rNO = 0.755, p = 0.000) and MND (rNC = 0.643, p = 0.000; rNO = 0.634, p = 0.000). In the training cohort, the area under the curve (AUC) of the model was 0.769 (P < 0.001, 95%CI 0.620-0.919), which had a good degree of differentiation (Fig. 2a). The calibration curve showed good agreement between predicted and actual probability. CONCLUSION: The nuclear density measurement on SD-OCT images can serve as an objective and reliable indicator for quantifying nuclear density.

Analytical validation of the DropXpert S6 system for diagnosis of chronic myelocytic leukemia.

Digital PCR is a powerful method for absolute nucleic acid quantification and is widely used in the absolute quantification of viral copy numbers, tumor marker detection, and prenatal diagnosis. However, for most of the existing droplet-based dPCR systems, the droplet generation, PCR reaction, and droplet detection are performed separately using different instruments. Making digital PCR both easy to use and practical by integrating the qPCR workflow into a superior all-in-one walkaway solution is one of the core ideas. A new innovative and integrated digital droplet PCR platform was developed that utilizes cutting-edge microfluidics to integrate dPCR workflows onto a single consumable chip. This makes previously complex workflows fast and simple; the whole process of droplet generation, PCR amplification, and droplet detection is completed on one chip, which meets the clinical requirement of "sample in, result out". It provides high multiplexing capabilities and strong sensitivity while all measurements were within the 95% confidence interval. This study is the first validation of the DropXpert S6 system and focuses primarily on verifying its reliability, repeatability, and consistency. In addition, the accuracy, detection limit, linearity, and precision of the system were evaluated after sample collection. Among them, the accuracy assessment by calculating the absolute bias of each target gene yielded a range from -0.1 to 0.08, all within ±0.5 logarithmic orders of magnitude; the LOB for the assay was set at 0, and the LoD value calculated using probit curves is MR4.7 (0.002%); the linearity evaluation showed that the R2 value of the BCR-ABL was 0.9996, and the R2 value of the ABL metrics calculated using the ERM standard was 0.9999; and the precision evaluation showed that all samples had a CV of less than 4% for intra-day, inter-day, and inter-instrument variation. The CV of inter-batch variation was less than 7%. The total CV was less than 5%. The results of the study demonstrate that dd-PCR can be applied to molecular detection and the clinical evaluation of CML patients and provide more precise personal treatment guidance, and its reproducibility predicts the future development of a wide range of clinical applications.

Prognostic significance and immune landscape of a cell cycle progression-related risk model in bladder cancer.

BACKGROUND: A greater emphasis has been placed on the part of cell cycle progression (CCP) in cancer in recent years. Nevertheless, the precise connection between CCP-related genes and bladder cancer (BCa) has remained elusive. This study endeavors to establish and validate a reliable risk model incorporating CCP-related factors, aiming to predict both the prognosis and immune landscape of BCa. METHODS: Clinical information and RNA sequencing data were collected from the GEO and TCGA databases. Univariate and multivariate Cox regression analyses were conducted to construct a risk model associated with CCP. The performance of the model was assessed using ROC and Kaplan-Meier survival analyses. Functional enrichment analysis was employed to investigate potential cellular functions and signaling pathways. The immune landscape was characterized using CIBERSORT algorithms. Integration of the risk model with various clinical variables led to the development of a nomogram. RESULTS: To build the risk model, three CCP-related genes (RAD54B, KPNA2, and TPM1) were carefully chosen. ROC and Kaplan-Meier survival analysis confirm that our model has good performance. About immunological infiltration, the high-risk group showed decreased levels of regulatory T cells and dendritic cells coupled with increased levels of activated CD4 + memory T cells, M2 macrophages, and neutrophils. Furthermore, the nomogram showed impressive predictive power for OS at 1, 3, and 5 years. CONCLUSION: This study provides new insights into the association between the CCP-related risk model and the prognosis of BCa, as well as its impact on the immune landscape.

In vivo study of chelating agent-modified nano zero-valent iron: Biodistribution and toxicity in mice.

In this study, the distribution and toxicity of nanoscale zero valent iron (nZVI) and nZVIs coated with citric acid and sodium tripolyphosphate (CA-nZVI and STPP-nZVI) in mice were investigated. nZVIs were primarily found in the livers and spleens, followed by the lungs, hearts, and kidneys. Histologic analysis revealed no significant histopathologic abnormalities or lesions in all organs except the liver at 14th d gavage. nZVIs did not have a noticeable impact on the body weight of the mice or the weight of their organs. Compared with the control group, there were no significant changes in hematology indexes in the nZVIs groups. However, the nZVIs groups exhibited varying levels of elevation in alanine aminotransferase, aspartate aminotransferase, and creatinine, suggesting liver and kidney inflammation in mice. The up-regulation of Nuclear Factor erythroid 2-Related Factor 2 and Heme oxygenase 1 in the nZVIs groups may be a response to nZVIs-induced oxidative stress. Immunohistochemical analysis confirmed the inflammatory response induced by the three nZVI groups. Chelating agents did not have a significant impact on the distribution or toxicity of nZVIs in mice. This study contributes to a comprehensive and detailed insight into nZVI toxicity in the environmental field.

CPSF3 regulates alternative polyadenylation of CNIH2 to promote esophageal squamous cell carcinoma progression.

Alternative polyadenylation (APA), an important post-transcriptional regulatory mechanism, is aberrantly activated in cancer，but how APA functions in tumorigenesis remains elusive. We analyzed APA events in RNA-seq data in TCGA and reported 3'UTR alterations associated with esophageal squamous cell carcinoma (ESCC) patient prognosis and gene expression changes involving loss of tumor-suppressive miRNA binding sites. Moreover, we investigated the expression and function of cleavage and polyadenylation specific factor 3 (CPSF3), a key APA regulator in ESCC. By immunohistochemistry and qRT-PCR, we found that CPSF3 was highly expressed in ESCC tissues and associated with poor patient prognosis. Overexpression of CPSF3 enhanced, while knockdown of CPSF3 inhibited ESCC cell proliferation and migration in vitro and in vivo, as determined by colony formation, transwell assays and animal experiments. Iso-Seq and RNA-seq data analysis indicated that knockdown of CPSF3 favored use of the distal poly (A) site in the 3'UTR of Cornichon family AMPA receptor auxiliary protein 2 (CNIH2), resulting in a long-3'UTR CNIH2 isoform that produced less CNIH2 protein due to miR-125a-5p targeting and downregulating CNIH2 mRNA through a miR-125a-5p binding site in the long CNIH2 mRNA 3'UTR. Moreover, CPSF3-induced ESCC tumorigenicity was mediated by CNIH2. Taken together, CPSF3 promotes ESCC progression by upregulating CNIH2 expression through loss of miR-125a-5p-mediated CNIH2 repression through alternative splicing and polyadenylation of the CNIH2 mRNA 3'UTR.

Phenolic constituents with potent α-glucosidase inhibitory and cytotoxic activities from Rumex nepalensis var. remotiflorus.

Quantitative analysis of Rumex nepalensis var. remotiflorus revealed that its roots contain rich anthraquinones, which has emodin, chrysophanol, and physcion contents of up to 0.30, 0.67, and 0.98 mg/g, respectively. Further phytochemical study led to the isolation and purification of seven undescribed phenolic constituents, including one flavan derivative with a 13-membered ring, polygorumin A (1), two dianthrone glucosides, polygonumnolides F and G (2, 3), two diphenylmethanones, rumepalens A and B (4, 5), and a pair of epimeric oxanthrone C-glucosides, rumejaposides K and L (6a, 6b) from the roots of R. nepalensis var. remotiflorus. Furthermore, 1 undescribed natural product, 1-ß-D-glucoside-6'-[(2E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate]-3-hydroxy-5-methylphenyl (19), and 21 known phenolic compounds were obtained from the aforementioned plant for the first time. Their structures were elucidated through extensive spectroscopic data analysis. Notably, compounds 1, 4-5, and 7-9 exhibited inhibitory activity on α-glucosidase with IC50 values ranging from 1.61 ± 0.17 to 32.41 ± 0.87 µM. In addition, the isolated dianthrone, chrysophanol bianthrone (14), showed obvious cytotoxicity against four human cancer cell lines (HL-60, SMMC-7721, A-549, and MDA-MB-231) with IC50 values ranging from 3.81 ± 0.17 to 35.15 ± 2.24 µM. In silico target prediction and molecular docking studies demonstrated that the mechanism of the anticancer activity of 14 may be related to the interaction with protein kinase CK2.

A first comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas.

Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new oncogene. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein (MFRP), by sponging the tumor suppressor microRNA miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.

Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model.

BACKGROUND: The pentose phosphate pathway (PPP) plays a crucial role in the material and energy metabolism in cancer cells. Targeting 6-phosphogluconate dehydrogenase (6PGD), the rate-limiting enzyme in the PPP metabolic process, to inhibit cellular metabolism is an effective anticancer strategy. In our previous study, we have preliminarily demonstrated that gambogic acid (GA) induced cancer cell death by inhibiting 6PGD and suppressing PPP at the cellular level. However, it is unclear whether GA could suppress cancer cell growth by inhibiting PPP pathway in mouse model. PURPOSE: This study aimed to confirm that GA as a covalent inhibitor of 6PGD protein and to validate that GA suppresses cancer cell growth by inhibiting the PPP pathway in a mouse model. METHODS: Cell viability was detected by CCK-8 assays as well as flow cytometry. The protein targets of GA were identified using a chemical probe and activity-based protein profiling (ABPP) technology. The target validation was performed by in-gel fluorescence assay, the Cellular Thermal Shift Assay (CETSA). A lung cancer mouse model was constructed to test the anticancer activity of GA. RNA sequencing was performed to analyze the global effect of GA on gene expression. RESULTS: The chemical probe of GA exhibited high biological activity in vitro. 6PGD was identified as one of the binding proteins of GA by ABPP. Our findings revealed a direct interaction between GA and 6PGD. We also found that the anti-cancer activity of GA depended on reactive oxygen species (ROS), as evidenced by experiments on cells with 6PGD knocked down. More importantly, GA could effectively reduce the production of the two major metabolites of the PPP in lung tissue and inhibit cancer cell growth in the mouse model. Finally, RNA sequencing data suggested that GA treatment significantly regulated apoptosis and hypoxia-related physiological processes. CONCLUSION: These results demonstrated that GA was a covalent inhibitor of 6PGD protein. GA effectively suppressed cancer cell growth by inhibiting the PPP pathway without causing significant side effects in the mouse model. Our study provides in vivo evidence that elucidates the anticancer mechanism of GA, which involves the inhibition of 6PGD and modulation of cellular metabolic processes.

Biomaterial-Based CRISPR/Cas9 Delivery Systems for Tumor Treatment.

CRISPR/Cas9 gene editing technology is characterized by high specificity and efficiency, and has been applied to the treatment of human diseases, especially tumors involving multiple genetic modifications. However, the clinical application of CRISPR/Cas9 still faces some major challenges, the most urgent of which is the development of optimized delivery vectors. Biomaterials are currently the best choice for use in CRISPR/Cas9 delivery vectors owing to their tunability, biocompatibility, and efficiency. As research on biomaterial vectors continues to progress, hope for the application of the CRISPR/Cas9 system for clinical oncology therapy builds. In this review, we first detail the CRISPR/Cas9 system and its potential applications in tumor therapy. Then, we introduce the different delivery forms and compare the physical, viral, and non-viral vectors. In addition, we analyze the characteristics of different types of biomaterial vectors. We further review recent research progress in the use of biomaterials as vectors for CRISPR/Cas9 delivery to treat specific tumors. Finally, we summarize the shortcomings and prospects of biomaterial-based CRISPR/Cas9 delivery systems.