DCAF7 Acts as A Scaffold to Recruit USP10 for G3BP1 Deubiquitylation and Facilitates Chemoresistance and Metastasis in Nasopharyngeal Carcinoma.

Despite docetaxel combined with cisplatin and 5-fluorouracil (TPF) being the established treatment for advanced nasopharyngeal carcinoma (NPC), there are patients who do not respond positively to this form of therapy. However, the mechanisms underlying this lack of benefit remain unclear. DCAF7 is identified as a chemoresistance gene attenuating the response to TPF therapy in NPC patients. DCAF7 promotes the cisplatin resistance and metastasis of NPC cells in vitro and in vivo. Mechanistically, DCAF7 serves as a scaffold protein that facilitates the interaction between USP10 and G3BP1, leading to the elimination of K48-linked ubiquitin moieties from Lys76 of G3BP1. This process helps prevent the degradation of G3BP1 via the ubiquitin‒proteasome pathway and promotes the formation of stress granule (SG)-like structures. Moreover, knockdown of G3BP1 successfully reversed the formation of SG-like structures and the oncogenic effects of DCAF7. Significantly, NPC patients with increased levels of DCAF7 showed a high risk of metastasis, and elevated DCAF7 levels are linked to an unfavorable prognosis. The study reveals DCAF7 as a crucial gene for cisplatin resistance and offers further understanding of how chemoresistance develops in NPC. The DCAF7-USP10-G3BP1 axis contains potential targets and biomarkers for NPC treatment.

Effectiveness and safety of brucea javanica oil assisted TACE versus TACE in the treatment of liver cancer: a systematic review and meta-analysis of randomized controlled trials.

Background: The effectiveness and safety of using Brucea javanica oil (BJO) in combination with Transarterial Chemoembolization (TACE) for liver cancer treatment are subjects of debate. This study aims to assess the comparative effectiveness and safety of BJO-assisted TACE versus TACE alone and quantifies the differences between these two treatment methods. Methods: A systematic search was conducted in multiple databases including PubMed, Cochrane, CNKI, and Wanfang, until 1 July 2023. Meta-analysis was conducted, and the results were presented as mean difference (MD), risk ratio (RR), and 95% confidence intervals (CI). Results: The search yielded 11 RCTs, with a combined sample size of 1054 patients. Meta-analysis revealed that BJO-assisted TACE exhibited superior outcomes compared to standalone TACE. Specific data revealed that BJO-assisted TACE improves clinical benefit rate by 22% [RR = 1.22, 95% CI (1.15, 1.30)], increases the number of people with improved quality of life by 32%, resulting in an average score improvement of 9.53 points [RR = 1.32, 95% CI (1.22, 1.43); MD = 9.53, 95% CI (6.95, 12.10)]. Furthermore, AFP improvement rate improved significantly by approximately 134% [RR = 2.34, 95% CI (1.58, 3.46)], accompanied by notable improvements in liver function indicators, with an average reduction of 27.19 U/L in AST [MD = -27.19, 95% CI (-40.36, -14.02)], 20.77 U/L in ALT [MD = -20.77, 95% CI (-39.46, -2.08)], 12.17 µmol/L in TBIL [MD = -12.17, 95% CI (-19.38, -4.97)], and a decrease of 43.72 pg/mL in VEGF [MD = -43.72, 95% CI (-63.29, -24.15)]. Most importantly, there was a 29% reduction in the occurrence of adverse reactions [RR = 0.71, 95% CI (0.60, 0.84)]. Conclusion: These findings indicate that BJO-assisted TACE may be considered as a potentially beneficial treatment option for liver cancer patients when compared to standalone TACE. It appears to contribute to improved treatment outcomes, enhanced quality of life, and potentially reduced adverse reactions, suggesting it warrants further investigation as a promising approach for liver cancer treatment. Systematic Review Registration: identifier CRD42023428948.

T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.

LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein.

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.

PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma.

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.

The immunotoxin targeting PRLR increases tamoxifen sensitivity and enhances the efficacy of chemotherapy in breast cancer.

BACKGROUND: Though tamoxifen achieves success in treating estrogen receptor α (ERα)-positive breast cancer, the followed development of tamoxifen resistance is a common challenge in clinic. Signals downstream of prolactin receptor (PRLR) could synergize with ERα in breast cancer progression. However, the potential effect of targeting PRL-PRLR axis combined with tamoxifen has not been thoroughly investigated. METHODS: High-throughput RNA-seq data obtained from TCGA, Metabric and GEO datasets were analyzed to explore PRLR expression in breast cancer cell and the association of PRLR expression with tamoxifen treatment. Exogenous or PRL overexpression cell models were employed to investigate the role of activated PRLR pathway in mediating tamoxifen insensitivity. Immunotoxin targeting PRLR (N8-PE24) was constructed with splicing-intein technique, and the efficacy of N8-PE24 against breast cancer was evaluated using in vitro and in vivo methods, including analysis of cells growth or apoptosis, 3D spheroids culture, and animal xenografts. RESULTS: PRLR pathway activated by PRL could significantly decrease sensitivity of ERα-positive breast cancer cells to tamoxifen. Tamoxifen treatment upregulated transcription of PRLR and could induce significant accumulation of PRLR protein in breast cancer cells by alkalizing lysosomes. Meanwhile, tamoxifen-resistant MCF7 achieved by long-term tamoxifen pressure exhibited both upregulated transcription and protein level of PRLR. Immunotoxin N8-PE24 enhanced sensitivity of breast cancer cells to tamoxifen both in vitro and in vivo. In xenograft models, N8-PE24 significantly enhanced the efficacy of tamoxifen and paclitaxel when treating PRLR-positive triple-negative breast cancer. CONCLUSIONS: PRL-PRLR axis potentially associates with tamoxifen insensitivity in ERα-positive breast cancer cells. N8-PE24 could inhibit cell growth of the breast cancers and promote drug sensitivity of PRLR-positive breast cancer cells to tamoxifen and paclitaxel. Our study provides a new perspective for targeting PRLR to treat breast cancer.

Correction: Zhao et al. Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN). Cells 2020, 9, 559.

In the original publication [...].

Risk of second primary thyroid cancer in cancer survivors.

A risk factor for thyroid cancer (TC) may be a history of former cancer and cancer therapy. The precise risk of a second primary thyroid carcinoma has not yet been revealed. In this study, we evaluated standardized incidence ratios (SIRs) of second primary thyroid cancer (SPTC) with consideration of different conditions and further analyzed the clinicopathological characteristics and survival of these patients. The cohort was selected from the US Surveillance, Epidemiology, and End Results (SEER) Program between 1975 and 2019. The standardized incidence ratios, morbidity risk, clinicopathological features, and survival of second primary thyroid carcinoma were analyzed. Propensity score matching (PSM) was used to balance covariates. Kaplan-Meier method was performed to assess the survival outcomes. Overall, 7066 patients with SPTC and 83,113 patients with primary TC were identified. The SIR of TC in tumor patients was 1.51/10,000, statistically higher than the natural population (0.94/10,000, P < 0.05). The most significant tumors contributing to the increased SIRs of SPTC were acute lymphocytic leukemia (3.49/10,000), Hodgkin's lymphoma-nodal (3.29/10,000), salivary gland cancer (3.23/10,000), and kidney and renal pelvis cancer (3.05/10,000). The incidence of TC increased significantly in tumor patients who received radiotherapy/chemotherapy before age 35. The age at diagnosis of the SPTC was much older than the primary TC (64.01 vs. 49.55 years, p < 0.001). The SPTC had a higher percentage of histological grades 3/4 (23.14% vs. 15.19%, p < 0.001). Survival analyses demonstrated a worse prognosis for the SPTC group compared to the primary TC group. But after PSM, the survival outcomes of the two groups tended to be equivalent (P = 0.584). The SIRs of TC are higher in tumor patients. The most significant factors contributing to the increased risk of SPTC were some specific former tumors and acceptance of radiotherapy/ chemotherapy before age 35. There was no significant difference in survival between SPTC and primary TC.

The survival after thyroidectomy versus lobectomy in multifocal papillary thyroid microcarcinoma patients.

BACKGROUND: The extent of thyroid surgery for multifocal papillary thyroid microcarcinoma (PTMC) remains controversial. Studies on the optimal surgical approach for a multifocal PTMC are scarce. This study aimed to compare the effectiveness of thyroidectomy and lobectomy for the treatment of multifocal PTMC. METHODS: A population-based retrospective cohort of patients with multifocal PTMC was analyzed using the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2017, and divided into two groups (thyroidectomy, lobectomy) based on the surgical approach. The clinicopathologic features and survival outcomes were compared between the two groups. Cox proportional hazards regression analysis to explore prognostic factors of survival. Propensity score matching (PSM) was used to balance covariates. RESULTS: Overall, a total of 9387 multifocal PTMC patients were included in the study. Among them, 8,107 (86.36%) patients received thyroidectomy, and 1280 (13.64%) patients underwent lobectomy. Compared to patients in the thyroidectomy group, patients in the lobectomy group were diagnosed with older age (50.47 years vs. 49.32 years, p = 0.003), a higher proportion of males (20.47% vs. 14.99%, p < 0.001), larger tumors (6.22 mm vs. 4.97 mm, p < 0.001), and more frequently underwent radiotherapy (35.40% vs. 10.16%, p < 0.001). Multivariate Cox regression analysis revealed that age was the only independent prognostic factor for thyroid cancer-specific survival (TCSS), and the determinants of overall survival (OS) were age and gender. Unadjusted survival analysis revealed no difference between the two treatment groups in TCSS (p = 0.598) and OS (p = 0.126). After 1:1 Propensity Score Matching (PSM), there was still no difference in TCSS (p = 0.368) or OS (p = 0.388). The stratified analysis revealed that for patients aged under or above 55, thyroidectomy was not associated with superior BCSS or OS (p > 0.05). CONCLUSIONS: Thyroidectomy was not associated with improved survival compared to thyroid lobectomy for patients with multifocal PTMC.

Characterization of a novel T cell-engaging bispecific antibody for elimination of L1CAM-positive tumors.

Neural cell adhesion molecule L1 (L1CAM) is a cell-surface glycoprotein involved in cancer occurrence and migration. Up to today, L1CAM-targeted therapy appeared limited efficacy in clinical trials although quite a few attempts by monoclonal antibody (mAb) or chimeric antigen receptor T-cell therapy (CAR-T) have been reported. Therefore, the development of new effective therapies targeting L1CAM is highly desirable. It has been demonstrated that T cell-engaging bispecific antibody (TCE) plays an effective role in cancer immunotherapy by redirecting the cytotoxic activity of CD3+ T cells to tumor cells, resulting in tumor cell death. In this study, we designed and characterized a novel bispecific antibody (CE7-TCE) based on the IgG-(L)-ScFv format, which targets L1CAM and CD3 simultaneously. In vitro, CE7-TCE induced specific killing of L1CAM-positive tumor cells through T cells. In vivo, CE7-TCE inhibited tumor growth in human peripheral blood mononuclear cell/tumor cell co-grafting models. To overcome the adaptive immune resistance (AIR) that impairs the efficacy of TCEs, we conducted a combination therapy of CE7-TCE with Pembrolizumab (anti-PD1 mAb), which enhanced the anti-tumor activity of CE7-TCE. Our results confirmed the feasibility of using L1CAM as a TCE target for the treatment of solid tumors and revealed the therapeutic potential of CE7-TCE combined with immune checkpoint inhibitors.

Oncolytic mineralized bacteria as potent locally administered immunotherapeutics.

Oncolytic bacteria can trigger innate immune activity. However, the antitumour efficacy of inactivated bacteria is poor, and attenuated live bacteria pose substantial safety risks. Here we show that intratumourally injected paraformaldehyde-fixed bacteria coated with manganese dioxide potently activate innate immune activity, modulate the immunosuppressive tumour microenvironment and trigger tumour-specific immune responses and abscopal antitumour responses. A single intratumoural administration of mineralized Salmonella typhimurium suppressed the growth of multiple types of subcutaneous and orthotopic tumours in mice, rabbits and tree shrews and protected the cured animals against tumour rechallenge. We also show that mineralized bacteria can be administered via arterial embolization to treat orthotopic liver cancer in rabbits. Our findings support the further translational testing of oncolytic mineralized bacteria as potent and safe antitumour immunotherapeutics.

CircCPA4 induces ASCT2 expression to promote tumor property of non-small cell lung cancer cells in a miR-145-5p-dependent manner.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a type of lung cancer that occurs in the cells of the respiratory tract, and its development is influenced by the regulation of circular RNAs (circRNAs). However, the role of circRNA carboxypeptidase A4 (circCPA4) in the progression of NSCLC and the underlying mechanism remain relatively clear. METHODS: The study utilized both real-time quantitative polymerase chain reaction (RT-qPCR) and western blot techniques to evaluate the levels of circCPA4, microRNA-145-5p (miR-145-5p), alanine, serine, or cysteine-preferring transporter 2 (ASCT2). To assess cell proliferation, cell counting kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were performed. Apoptosis was determined using flow cytometry, while cell migration and invasive capacity were evaluated through transwell and wound-healing assays. Intracellular levels of glutamine, glutamate, and α-KG were measured using specific kits. The relationship between miR-145-5p and circCPA4 or ASCT2 was confirmed using dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: CircCPA4 and ASCT2 RNA levels were elevated, while miR-145-5p was downregulated in both NSCLC tissues and cells. Depletion of circCPA4 significantly inhibited NSCLC cell proliferation, migration, invasion, and intracellular levels of glutamine, glutamate, and α-KG, and promoted apoptosis. Moreover, circCPA4 knockdown delayed tumor growth in vivo. Furthermore, circCPA4 was found to bind to miR-145-5p, thereby regulating the progression of NSCLC in vitro. ASCT2 was also identified as a downstream target of miR-145-5p, and its upregulation rescued the effects of miR-145-5p overexpression on NSCLC cell processes. CONCLUSION: CircCPA4 knockdown inhibited tumor property of NSCLC cells by modulating the miR-145-5p/ASCT2 axis.

Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma.

Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.

Ferroptosis Exists in Ischemia Reperfusion Injury after Cardiac Surgery with Cardiopulmonary Bypass.

Ischemia-reperfusion (IR) injury commonly arises during cardiac surgery involving Cardiopulmonary Bypass (CPB), and it has relationship with ferroptosis in mice. However, the exact role of ferroptosis in the human cardiac damage caused by cardiac surgery remains unclear. Basic patient data and perioperative period information were collected, and clinic indicators related to cardiac function were detected to assess the extent of cardiac injury. Cardiac tissue samples were collected to determine histopathological changes, ultrastructure of mitochondrial and hallmarks of ferroptosis. 25 patients were involved in this study. In the present study, we observed a significant increase in the clinical indicator hs-cTnT, with levels rising more than 1393 ± 242 folds (P < 0.0001) following the cardiac surgery. Masson staining revealed a notable increase in fibrosis levels by 2.282 ± 0.259% (P = 0.0009). Furthermore, there was a significant elevation in lipid peroxidation, as evidenced by a 61.42 ± 17.33% increase in MDA (P = 0.0006). Additionally, we observed notable swelling, decreased mitochondrial crista, and even fragmented mitochondria. Notably, changes in the marker gene of ferroptosis were observed, with PTGS2 showing a 6.437 ± 0.81 folds increase (P < 0.0001). Furthermore, key regulators such as SLC7A11 and GPX4 proteins exhibited a reduction of 97.33 ± 25.78% (P = 0.0068) and 60.59 ± 14.93% (P = 0.0071), respectively, indicating the occurrence of ferroptosis following the surgery. Ferroptosis exists in myocardial IR injury caused by cardiac surgery with CPB, indicating that targeting ferroptosis could serve as a potential strategy for myocardial protection against CPB-induced IR injury. The trial has been registered in Chinese Clinical Trial Registry (ChiCTR, No. ChiCTR2200061995) on July 16th, 2022.

Construction and validation of a nomogram for predicting lateral lymph node metastasis in pediatric and adolescent with differentiated thyroid carcinoma.

BACKGROUND: Limited research has been conducted to specifically investigate the identification of risk factors and the development of prediction models for lateral lymph node metastasis (LNM) in pediatric and adolescent differentiated thyroid carcinoma (DTC) populations, despite its significant association with unfavorable prognosis. METHODS: This study entails a retrospective analysis of the clinical characteristics exhibited by pediatric and adolescent patients who have been diagnosed with DTC. The data utilized for this analysis was sourced from the Surveillance, Epidemiology, and End Results (SEER) database, spanning the time frame from 2000 to 2020. Furthermore, the study incorporates patients who were treated at the Departments of Breast and Thyroid Surgery in the Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine, as well as The General Hospital of Western Theater Command, during the period from 2010 to 2020. RESULTS: A cohort of 2631 patients from the SEER database, along with an additional 339 patients from our departments who met the specified inclusion criteria, were included in this study. Subsequently, four clinical variables, namely age, tumor size, multifocality, and extrathyroidal invasion, were identified as being significantly associated with lateral LNM in pediatric and adolescent DTC patients. These variables were then utilized to construct a nomogram, which demonstrated effective discrimination with a concordance index (C-index) of 0.731. Furthermore, the performance of this model was validated through both internal and external assessments, yielding C-index values of 0.721 and 0.712, respectively. Afterward, a decision curve analysis was conducted to assess the viability of this nomogram in predicting lymph node metastasis. CONCLUSION: The current investigation has effectively constructed a nomogram model utilizing visualized multipopulationsal data. Our findings demonstrate a significant association between various clinical characteristics and lateral LNM in pediatric and adolescent DTC patients. These outcomes hold substantial significance for healthcare practitioners, as they can employ this model to inform individualized clinical judgments for the pediatric and adolescent cohorts.

Synthesis, antitumor activity evaluation of 2-selenocyano-3-selenocyanoalkyloxyestradiols with a bisselenocyanate structure.

The combination of steroid structure and selenocyano group offers high potential for the design and synthesis of new potential anti-tumor drugs. Beginning with estradiol, a series of 2-selenocyano-3-selenocyanoalkyloxyestradiol derivatives with remarkable antiproliferative activity was synthesized. Additionally, a 2,4-bisselenocyanoestradiol was synthesized by directly selenocyanating estradiol diacetate. It was found that the cytotoxicity of 2-selenocyano-3-selenocyanoalkyloxyestradiol derivatives was significantly increased in comparison to the corresponding monoselenocyanate precursor, whereas the cytotoxicity of the 2, 4-bisselenocyanoestradiol derivative was significantly reduced compared to the respective monosubstituted precursor. The introduction of the second selenocyano group at different locations of estradiol shows a various impact on the cytotoxicity of the compounds. Among them, compound 3e showed the best cytotoxicity, with an IC50 value of less than 5 µM against the tested tumor cells, and strong inhibitory activities against HeLa and MCF-7 cell xenograft tumors in zebrafish, suppressing tumor cell migration and neovascularization. Notably, compound 3e was more effective at inhibiting neovascularization of MCF-7 cell xenograft tumors than the positive control 2-methoxyestradiol. Furthermore, compound 3e showed excellent anti-oxidative stress effect in zebrafish. Therefore, these estrogen bisselenocyanate compounds may be promising anti-tumor agents, warranting further investigation.

Fisetin, a dietary flavonoid, promotes transintestinal cholesterol excretion through the activation of PPARδ.

Fisetin, a dietary polyphenol abundantly found in strawberries, exhibits a broad spectrum of health-promoting activities, including antihyperlipidemic effects. This study aimed to investigate the regulatory effect of fisetin on cholesterol elimination through novel transintestinal cholesterol excretion (TICE) pathway. A hypercholesterolemic mouse model and human colon epithelial cancer cell line Caco-2 were utilized to conduct the study. In hypercholesterolemic mice, fisetin (25 mg/kg) treatment reduced serum total cholesterol by 46.48% and significantly decreased lipid accumulation in the liver. Furthermore, fisetin administration led to a substantial increase in the fecal neutral sterol contents, including coprostanol, coprostanone, dihydrocholesterol, and cholesterol. Specifically, these sterol contents increased by approximately 224.20%, 151.40%, 70.40% and 50.72% respectively. The fluorescence intensity of 22-NBD-cholesterol in intestinal perfusion increased by 95.94% in fisetin group (25 mg/kg), indicating that fisetin stimulated TICE. In high cholesterol-induced Caco-2 cells, fisetin at a concentration of 30 µM reduced total cholesterol and free cholesterol by 37.21% and 45.30% respectively, stimulated cholesterol excretion, and inhibited cholesterol accumulation. Additionally, fisetin upregulated the gene and protein expression of cholesterol efflux transporters ABCG5/G8 and ABCB1, while downregulating the cholesterol uptake regulator NPC1L1. Furthermore, fisetin increased LDLR protein expression and decreased PCSK9 expression. Notably, fisetin significantly activated nuclear receptor PPARδ in Caco-2 cells. PPARδ antagonist pretreatment counteracted the regulatory effects of fisetin on TICE regulators, suggesting fisetin lowered cholesterol through enhancing TICE by activation of intestinal PPARδ. Fisetin could be used as functional dietarysupplement for eliminating cholesterol and reducing the incidence of cardiovascular diseases.

Ojeok-san enhances platinum sensitivity in ovarian cancer by regulating adipocyte paracrine IGF1 secretion.

BACKGROUND: Platinum is a commonly used drug for ovarian cancer (OvCa) treatment, but drug resistance limits its clinical application. This study intended to delineate the effects of adipocytes on platinum resistance in OvCa. METHODS: OvCa cells were maintained in the adipocyte-conditioned medium. Cell viability and apoptosis were detected by CCK-8 and flow cytometry, separately. Proliferation and apoptosis-related protein expression were assayed by western blot. The IC50 values of cisplatin and carboplatin were determined using CCK-8. IGF1 secretion and expression were assayed via ELISA and western blot, respectively. A xenograft model was established, and pathological changes were detected by H&E staining. Proliferation and apoptosis-associated protein expression was assessed via IHC. RESULTS: Adipocytes promoted the viability and repressed cell apoptosis in OvCa, as well as enhancing platinum resistance, while the addition of IGF-1 R inhibitor reversed the effects of adipocytes on proliferation, apoptosis, and drug resistance of OvCa cells. Treatment with different concentrations of Ojeok-san (OJS) inhibited the adipocyte-induced platinum resistance in OvCa cells by suppressing IGF1. The combined treatment of OJS and cisplatin significantly inhibited tumour growth in vivo with good mouse tolerance. CONCLUSION: In summary, OJS inhibited OvCa proliferation and platinum resistance by suppressing adipocyte paracrine IGF1 secretion.

Identification of key immune cell-related genes involved in tumorigenesis and prognosis of cervical squamous cell carcinoma.

The infiltration of immune cells can significantly affect the prognosis and immune therapy of patients with cervical squamous cell carcinoma (CSCC). This study aimed to explore key immune cell-related genes in the tumorigenesis and prognosis of CSCC. The module significantly related to immunity was screened by weighted gene co-expression network analysis (WGCNA) and ESTIMATE analysis, followed by correlation analysis with clinical traits. Key candidate genes were intersected with the protein-protein interaction (PPI) network genes for immune-related genes. The relationship between immune cell infiltration and key genes was analyzed. Tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) predicted the response to immunotherapy in CSCC patients. Clinically, quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry were manipulated for analyzing the changes in mRNA and protein expression of key genes in cancer. Western blot was conducted to assess the correlation between key genes and immune infiltration. The brown module was notably associated with the immune microenvironment of CSCC, from which three immune-related key genes (TYROBP, CCL5, and HLA-DRA) were obtained. High expression of these genes was significantly positively associated with the infiltration abundance of T cells, B cells, and other immune cells. High expression levels of three key genes were confirmed in para-cancer tissue and correlated with the abundance of immune cells. The high-expression group of key genes was more sensitive to immunotherapy. We provide a theoretical basis for searching for potential targets for effective treatment and diagnosis of CSCC and provide new ideas for developing novel immunotherapy strategies.

Research progress on vesicles from Chinese medicinal herbs. / æ¤ç‰©ç±»ä¸­è¯æ¥æºå›Šæ³¡çš„ç ”ç©¶è¿›å±•.

Vesicles derived from Chinese medicinal herbs (VCMH) are nano-vesicular entities released by the cells of Chinese medicinal herbs. VCMHs have various biological effects and targeting characteristics, and their component chemicals and functional activities are closely related to the parent plant. VCMH differs from animal-derived vesicles in three ways: stability, specificity, and safety. There are a number of extraction and isolation techniques for VCMH, each with their own benefits and drawbacks, and there is no unified standard. When two or more approaches are used, high quantities of intact vesicles can be obtained more quickly and efficiently. The obtained VCMHs were systematically examined and evaluated. Firstly, they are generally saucer-shaped, cup-shaped or sphere, with particle size of 10-300 nm. Secondly, they contain lipids, proteins, nucleic acids and other active substances, and these components are an important part for intercellular information transfer. Finally, they mostly have good biocompatibility and low toxicity, with anti-inflammatory, antioxidant, anti-tumor and anti-fibrotic effects. As a new drug carrier, VCMHs have outstanding active targeting capabilities, and the capsule form can effectively preserve the drugs, considerably enhancing drug delivery efficiency and stability in vitro and in vivo. The modification of its vesicular structure by suitable physical or chemical means can further create more stable and precise drug carriers. This article reviews the extraction and purification techniques, activity evaluation and application of VCMH to provide information for further research and application of new active substances and targeted drug carriers.