Treating cancer through modulating exosomal protein loading and function: The prospects of natural products and traditional Chinese medicine.

Exosomes, small yet vital extracellular vesicles, play an integral role in intercellular communication. They transport critical components, such as proteins, lipid bilayers, DNA, RNA, and glycans, to target cells. These vesicles are crucial in modulating the extracellular matrix and orchestrating signal transduction processes. In oncology, exosomes are pivotal in tumor growth, metastasis, drug resistance, and immune modulation within the tumor microenvironment. Exosomal proteins, noted for their stability and specificity, have garnered widespread attention. This review delves into the mechanisms of exosomal protein loading and their impact on tumor development, with a focus on the regulatory effects of natural products and traditional Chinese medicine on exosomal protein loading and function. These insights not only offer new strategies and methodologies for cancer treatment but also provide scientific bases and directions for future clinical applications.

A review of chemotherapeutic drugs-induced arrhythmia and potential intervention with traditional Chinese medicines.

Significant advances in chemotherapy drugs have reduced mortality in patients with malignant tumors. However, chemotherapy-related cardiotoxicity increases the morbidity and mortality of patients, and has become the second leading cause of death after tumor recurrence, which has received more and more attention in recent years. Arrhythmia is one of the common types of chemotherapy-induced cardiotoxicity, and has become a new risk related to chemotherapy treatment, which seriously affects the therapeutic outcome in patients. Traditional Chinese medicine has experienced thousands of years of clinical practice in China, and has accumulated a wealth of medical theories and treatment formulas, which has unique advantages in the prevention and treatment of malignant diseases. Traditional Chinese medicine may reduce the arrhythmic toxicity caused by chemotherapy without affecting the anti-cancer effect. This paper mainly discussed the types and pathogenesis of secondary chemotherapeutic drug-induced arrhythmia (CDIA), and summarized the studies on Chinese medicine compounds, Chinese medicine Combination Formula and Chinese medicine injection that may be beneficial in intervention with secondary CDIA including atrial fibrillation, ventricular arrhythmia and sinus bradycardia, in order to provide reference for clinical prevention and treatment of chemotherapy-induced arrhythmias.

Immune-related LncRNAs scores predicts chemotherapeutic responses and prognosis in cervical cancer patients.

BACKGROUND: Long non-coding RNAs (LncRNAs) regulating the immune microenvironment of cancer is a hot spot. But little is known about the influence of the immune-related lncRNA (IRlncRs) on the chemotherapeutic responses and prognosis of cervical cancer (CC) patients. The purpose of the study was to identify an immune-related lncRNAs (IRlncRs)-based model for the prospective prediction of clinical outcomes in CC patients. METHODS: CC patients' relevant data was acquired from The Cancer Genome Atlas (TCGA). Correlation analysis and Cox regression analyses were applied. A risk score formula was formulated. Prognostic factors were combined into a nomogram, while sensitivity for chemotherapy drugs was analyzed using the OncoPredict algorithm. RESULTS: Eight optimal IRlncRs(ATP2A1-AS1, LINC01943, AL158166.1, LINC00963, AC009065.8, LIPE-AS1, AC105277.1, AC098613.1.) were incorporated in the IRlncRs model. The overall survival (OS) of the high-risk group of the model was inferior to those in the low-risk group. Further analysis demonstrated this eight-IRlncRs model as a useful prognostic marker. The Nomogram had a concordance index of survival prediction of 0.763(95% CI 0.746-0.780) and more robust predictive accuracy. Furthermore, patients in the low-risk group were found to be more sensitive to chemotherapy, including Paclitaxel, Rapamycin, Epirubicin, Vincristine, Docetaxel and Vinorelbine. CONCLUSIONS: An eight-IRlncRs-based prediction model was identified that has the potential to be an important tool to predict chemotherapeutic responses and prognosis for CC patients.

Three-in-One Peptide Prodrug with Targeting, Assembly and Release Properties for Overcoming Bacterium-Induced Drug Resistance and Potentiating Anti-Cancer Immune Response.

The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate antitumor immunity, herein a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) is rationally designed containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic Cip-OH and chemotherapeutic drug CPT are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment.

Leaf Extract from European Olive (Olea europaea L.) Post-Transcriptionally Suppresses the Epithelial-Mesenchymal Transition and Sensitizes Gastric Cancer Cells to Chemotherapy.

The overall survival of patients with the advanced and recurrent gastric cancer (GC) remains unfavorable. In particular, this is due to cancer spreading and resistance to chemotherapy associated with the epithelial-mesenchymal transition (EMT) of tumor cells. EMT can be identified by the transcriptome profiling of GC for EMT markers. Indeed, analysis of the TCGA and GTEx databases (n = 408) and a cohort of GC patients (n = 43) revealed that expression of the CDH2 gene was significantly decreased in the tumors vs. non-tumor tissues and correlated with the overall survival of GC patients. Expression of the EMT-promoting transcription factors SNAIL and ZEB1 was significantly increased in GC. These data suggest that targeting the EMT might be an attractive therapeutic approach for patients with GC. Previously, we demonstrated a potent anti-cancer activity of the olive leaf extract (OLE). However, its effect on the EMT regulation in GC remained unknown. Here, we showed that OLE efficiently potentiated the inhibitory effect of the chemotherapeutic agents 5-fluorouracil (5-FU) and cisplatin (Cis) on the EMT and their pro-apoptotic activity, as was demonstrated by changes in the expression of the EMT markers (E- and N-cadherins, vimentin, claudin-1) in GC cells treated with the aforementioned chemotherapeutic agents in the presence of OLE. Thus, culturing GC cells with 5-FU + OLE or Cis + OLE attenuated the invasive properties of cancer cells. Importantly, upregulation of expression of the apoptotic markers (PARP cleaved form) and increase in the number of cells undergoing apoptosis (annexin V-positive) were observed for GC cells treated with a combination of OLE and 5-FU or Cis. Collectively, our data illustrate that OLE efficiently interferes with the EMT in GC cells and potentiates the pro-apoptotic activity of certain chemotherapeutic agents used for GC therapy.

Antiproliferative activities of some selected Nigerian medicinal plants against breast, liver, and cervical cancer cells.

BACKGROUND: Phytochemicals have become a growing source of alternative medicine in developing countries due to the poor prognosis, high cost of conventional pharmaceuticals, and undesirable effects associated with mainstream cancer treatment. OBJECTIVE: This study was aimed at investigating the anticancer effect of some selected Nigerian medicinal plants used in cancer treatment. These include ethanol extracts of Dialium guineense root (DGR), Dialium guineense leaves (DGL), Jateorhiza macrantha leaves (JML), Musanga cecropioides leaves (MCL), Musanga cecropioides stembark (MCSB), Piptadeniastrum africanum stembark (PASB), Piptadeniastrum africanum root (PAR), Pupalia lappacea flower tops (PLF), Raphiostylis beninensis root (RBR), Raphiostylis beninensis leaves (RBL), Ritchiea capparoides leaves (RCL), Ritchiea capparoides stembark (RCSB), and Triplochiton scleroxylon stembark (TSB). METHODS: The cytotoxic activity of the extracts was examined using a brine shrimp lethality assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against three cancer cell lines, including MCF-7, HUH-7, and HeLa. The selectivity of all extracts towards cancer cells was investigated using normal lung fibroblasts (MRC-5). Cell migration and colony-forming assays of active extracts against MCF-7 cells were also performed. Additionally, the total polyphenolic contents of the active extracts were estimated using standard methods. RESULTS: The extract of PASB had the highest cytotoxicity (LC50 = 1.58 µg/mL) on the brine shrimps compared to vincristine sulphate (LC50 = 2.24 µg/mL). In the cell viability assay, all the extracts produced significant (p < 0.05) growth inhibitory effects against all cell lines tested in a dose-dependent manner. All extracts were selective to cancer cells at varying degrees. Worth mentioning are the extracts of MCL, DGR, RBR, and PASB, which exhibited 14-, 7-, 6- and 2-fold selectivity toward MCF-7 cancer cells relative to normal lung fibroblast (MRC-5), respectively. These four extracts also significantly inhibited cell migration and colony formation in MCF-7-treated cells in dose-dependent manners. Considerable amounts of phenolics, flavonoids, and proanthocyanidins were detected in all extracts evaluated. CONCLUSION: These findings advocate the continued development of MCL, DGR, RBR, and PASB as potential chemotherapeutic agents.

Carboplatin in Patients With Metastatic Castration-Resistant Prostate Cancer Harboring Somatic or Germline Homologous Recombination Repair Gene Mutations: Phase II Single-Arm Trial.

BACKGROUND: Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations. OBJECTIVE: The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin. METHODS: Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0). RESULTS: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan. CONCLUSIONS: This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54086.

Nanomedicines: Emerging Platforms in Smart Chemotherapy Treatment-A Recent Review.

Cancer continues to pose one of the most critical challenges in global healthcare. Despite the wide array of existing cancer drugs, the primary obstacle remains in selectively targeting and eliminating cancer cells while minimizing damage to healthy ones, thereby reducing treatment side effects. The revolutionary approach of utilizing nanomaterials for delivering cancer therapeutic agents has significantly enhanced the efficacy and safety of chemotherapeutic drugs. This crucial shift is attributed to the unique properties of nanomaterials, enabling nanocarriers to transport therapeutic agents to tumor sites in both passive and active modes, while minimizing drug elimination from delivery systems. Furthermore, these nanocarriers can be designed to respond to internal or external stimuli, thus facilitating controlled drug release. However, the production of nanomedications for cancer therapy encounters various challenges that can impede progress in this field. This review aims to provide a comprehensive overview of the current state of nanomedication in cancer treatment. It explores a variety of nanomaterials, focusing on their unique properties that are crucial for overcoming the limitations of conventional chemotherapy. Additionally, the review delves into the properties and functionalities of nanocarriers, highlighting their significant impact on the evolution of nanomedicine. It also critically assesses recent advancements in drug delivery systems, covering a range of innovative delivery methodologies. Finally, the review succinctly addresses the challenges encountered in developing nanomedications, offering insightful perspectives to guide future research in this field.

Compound Z526 alleviates chemotherapy-induced cachectic muscle loss by ameliorating oxidative stress-driven protein metabolic imbalance and apoptosis.

Chemotherapy is one of the primary and indispensable intervention against cancers though it is always accompanied by severe side effects especially cachexia. Cachexia is a fatal metabolic disorder syndrome, mainly characterized by muscle loss. Oxidative stress is the key factor that trigger cachectic muscle loss by inducing imbalance in protein metabolism and apoptosis. Here, we showed an oral compound (Z526) exhibited potent alleviating effects on C2C12 myotube atrophy induced by various chemotherapeutic agents in vitro as well as mice muscle loss and impaired grip force induced by oxaliplatin in vivo. Furthermore, Z526 also could ameliorate C2C12 myotube atrophy induced by the combination of chemotherapeutic agents with conditioned medium of various tumor cells in vitro as well as mice muscle atrophy of C26 tumor-bearing mice treated with oxaliplatin. The pharmacological effects of Z526 were based on its potency in reducing oxidative stress in cachectic myocytes and muscle tissues, which inhibited the activation of NF-κB and STAT3 to decrease Atrogin-1-mediated protein degradation, activated the AKT/mTOR signaling pathway to promote protein synthesis, regulated Bcl-2/BAX ratio to reduce Caspase-3-triggered apoptosis. Our work suggested Z526 to be an optional strategy for ameliorating cachexia muscle atrophy in the multimodality treatment of cancers.

Phase II study of the novel antifolate agent pralatrexate in combination with the histone deacetylase inhibitor romidepsin for the treatment of patients with mature T-cell lymphoma.

Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies (N = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies.Trial Registration: www.clinicaltrials.gov (NCT01947140).

Current landscape of preoperative neoadjuvant therapies for initial resectable colorectal cancer liver metastasis.

Colorectal cancer liver metastasis (CRLM) presents a clinical challenge, and optimizing treatment strategies is crucial for improving patient outcomes. Surgical resection, a key element in achieving prolonged survival, is often linked to a heightened risk of recurrence. Acknowledging the potential benefits of preoperative neoadjuvant chemotherapy in managing resectable liver metastases, this approach has gained attention for its role in tumor downsizing, assessing biological behavior, and reducing the risk of postoperative recurrence. However, the use of neoadjuvant chemotherapy in initially resectable CRLM sparks ongoing debates. The balance between tumor reduction and the risk of hepatic injury, coupled with concerns about delaying surgery, necessitates a nuanced approach. This article explores recent research insights and draws upon the practical experiences at our center to address critical issues regarding considerations for initially resectable cases. Examining the criteria for patient selection and the judicious choice of neoadjuvant regimens are pivotal areas of discussion. Striking the right balance between maximizing treatment efficacy and minimizing adverse effects is imperative. The dynamic landscape of precision medicine is also reflected in the evolving role of gene testing, such as RAS/BRAF and PIK3CA, in tailoring neoadjuvant regimens. Furthermore, the review emphasizes the need for a multidisciplinary approach to navigate the complexities of CRLM. Integrating technical expertise and biological insights is crucial in refining neoadjuvant strategies. The management of progression following neoadjuvant chemotherapy requires a tailored approach, acknowledging the diverse biological behaviors that may emerge. In conclusion, this review aims to provide a comprehensive perspective on the considerations, challenges, and advancements in the use of neoadjuvant chemotherapy for initially resectable CRLM. By combining evidence-based insights with practical experiences, we aspire to contribute to the ongoing discourse on refining treatment paradigms for improved outcomes in patients with CRLM.

Construction of a necroptosis-related lncRNA signature for predicting prognosis and revealing the immune microenvironment in bladder cancer.

BACKGROUND: Bladder cancer (BCa) is a common malignancy in the urinary system. Necroptosis, a recently discovered form of programmed cell death, is closely associated with the development and progression of various types of tumors. Targeting necroptosis through anti-cancer strategies has shown potential as a therapy for cancer. We aimed to develop a necroptosis-related lncRNAs (NRlncRNAs) risk model that can predict the survival and tumor immunity of BCa patients. METHODS: We analyzed sequencing data obtained from the TCGA database, and applied least absolute shrinkage and selection operator (LASSO) and Cox regression analysis to identify crucial NRlncRNAs for building a risk model. Using the risk score, we categorized patients into high- and low-risk groups, and assessed the accuracy with the area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves. We performed the RT-qPCR to detect the expression differences of the genes based on the risk model. RESULTS: We identified a total of 296 NRlncRNAs, and 6 of them were included in the prognostic model. The AUC values for 1-, 3-, and 5-year predictions were 0.675, 0.726 and 0.734, respectively. Our risk model demonstrated excellent predictive performance and served as an independent predictor with high predictive power. Additionally, we performed PCA, TMB, GSEA analyses, and evaluated immune cell infiltration, to reveal significant differences between the high- and low-risk groups in functional signaling pathways, immunological status, and mutation profiles. Finally, we assessed the chemotherapeutic response of several drugs. According to the RT-qPCR results, we found that four NRlncRNAs of the risk model were more highly expressed in BCa cell lines than human immortalized uroepithelial cell line and regulated the occurrence and progression of bladder cancer. CONCLUSION: We constructed a novel NRlncRNAs-associated risk model, which could predict the prognosis and immune response of BCa patients.

MicroRNAs in adult high-grade gliomas: Mechanisms of chemotherapeutic resistance and their clinical relevance.

Notorious for its high mortality rate, the current standard treatment for high-grade gliomas remains a challenge. This is largely due to the complex heterogeneity of the tumour coupled with dysregulated molecular mechanisms leading to the development of drug resistance. In recent years, microRNAs (miRNAs) have been considered to provide important information about the pathogenesis and prognostication of gliomas. miRNAs have been shown to play a specific role in promoting oncogenesis and regulating resistance to anti-glioma therapeutic agents through diverse cellular mechanisms. These include regulation of apoptosis, alterations in drug efflux pathways, enhanced activation of oncogenic signalling pathways, Epithelial-Mesenchymal Transition-like process (EMT-like) and a few others. With this knowledge, upregulation or inhibition of selected miRNAs can be used to directly affect drug resistance in glioma cells. Moreover, the clinical use of miRNAs in glioma management is becoming increasingly valuable. This comprehensive review delves into the role of miRNAs in drug resistance in high-grade gliomas and underscores their clinical significance. Our analysis has identified a distinct cluster of oncogenic miRNAs (miR-9, miR-21, miR-26a, miR-125b, and miR-221/222) and tumour suppressive miRNAs (miR-29, miR-23, miR-34a-5p, miR 181b-5p, miR-16-5p, and miR-20a) that consistently emerge as key players in regulating drug resistance across various studies. These miRNAs have demonstrated significant clinical relevance in the context of resistance to anti-glioma therapies. Additionally, the clinical significance of miRNA analysis is emphasised, including their potential to serve as clinical biomarkers for diagnosing, staging, evaluating prognosis, and assessing treatment response in gliomas.

Anticancer and chemopreventive potential of Morinda citrifolia L. bioactive compounds: A comprehensive update.

Morinda citrifolia L., commonly known as Noni, has a longstanding history in traditional medicine for treating various diseases. Recently, there has been an increased focus on exploring Noni extracts and phytoconstituents, particularly for their effectiveness against cancers such as lung, esophageal, liver, and breast cancer, and their potential in cancer chemoprevention. This study aims to provide a comprehensive review of in vitro and in vivo studies assessing Noni's impact on cancer, alongside an exploration of its bioactive compounds. A systematic review was conducted, encompassing a wide range of scientific databases to gather pertinent literature. This review focused on in vitro and in vivo studies, as well as clinical trials that explore the effects of Noni fruit and its phytoconstituents-including anthraquinones, flavonoids, sugar derivatives, and neolignans-on cancer. The search was meticulously structured around specific keywords and criteria to ensure a thorough analysis. The compiled studies highlight Noni's multifaceted role in cancer therapy, showcasing its various bioactive components and their modes of action. This includes mechanisms such as apoptosis induction, cell cycle arrest, antiangiogenesis, and immune system modulation, demonstrating significant anticancer and chemopreventive potential. The findings reinforce Noni's potential as a safe and effective option in cancer prevention and treatment. This review underscores the need for further research into Noni's anticancer properties, with the hope of stimulating additional studies and clinical trials to validate and expand upon these promising findings.

Development of a novel senescence-related gene signature to predict clinical outcomes, immune landscape, and chemotherapeutic sensitivity in oral squamous cell carcinoma.

BACKGROUND: Cellular senescence significantly associates with tumor initiation, progression, and therapeutic response across multiple cancers. Here, we sought to develop a novel senescence-related genes (SRGs)-derived signature for oral squamous cell carcinoma (OSCC) prognostication and therapeutic response prediction. METHODS: OSCC-specific SRG prognostic signature was established with univariate Cox regression, Kaplan-Meier survival, and LASSO-penalized multivariate Cox regression analyses. A SRG nomogram integrating this signature and selected clinicopathological parameters were constructed by multivariate Cox regression. SiRNA-mediated gene knockdown was exploited to validate its function in vitro. The utilities of SRG signature in predicting immune status and chemotherapeutic sensitivities were analyzed. RESULTS: The prognostic performance of SRG signature/nomogram was satisfactory in multiple independent cohorts. CDK1 knockdown induced senescence phenotype in vitro. Moreover, SRG signature scores negatively correlated with tumor-infiltrating immune cells and associated with multiple chemotherapeutic drug sensitivities. CONCLUSIONS: Our results established SRG-derived signature/nomogram as powerful predictors for prognosis and chemotherapeutic response for OSCC.

Etoposide-induced SENP8 confers a feed-back drug resistance on acute lymphoblastic leukemia cells.

Chemotherapy is the most common treatment for acute lymphoblastic leukemia (ALL). However, many ALL patients eventually develop relapse and treating relapsed ALL has always been challenging. Therefore, exploring the resistance mechanism of chemotherapeutic drugs and proposing feasible intervention strategies are of great significance for ALL treatment. Here, we show that SENP8, whose coding protein is an important deNEDDylase targeting the substrate for deNEDDylation, is highly expressed in relapsed ALL specimens. Interestingly, overexpressing SENP8 specifically reduces the chemosensitivity of ALL cells to etoposide (VP-16) and significantly alleviates the proapoptotic effect of VP-16 on ALL cells. By contrast, NEDDylation inhibition reduces the chemosensitivity of ALL cells to VP-16. Furthermore, VP-16 induces SENP8 accumulation and the instability of MDM2 as well as the stabilization of p53 in ALL cells, and SENP8 knockdown can sensitize ALL cells to VP-16. Our study reveals a novel function of SENP8 in ALL and that VP-16-induced SENP8 confers a feed-back drug resistance on ALL cells, suggesting a possibility of overcoming the chemotherapeutic resistance to VP-16 via targeting SENP8.

Network Pharmacology and In vitro Experimental Verification to Explore the Mechanism of Chaiqin Qingning Capsule in the Treatment of Pain.

BACKGROUND: Chaiqin Qingning capsule (CQQNC) has been used to relieve pain in practice. However, the active components, pain targets, and molecular mechanisms for pain control are unclear. OBJECTIVE: To explore the active components and potential mechanisms of the analgesic effect of CQQNC through network pharmacology and in vitro experiments. METHODS: The main active components and the corresponding targets of CQQNC were screened from the TCMSP and the SwissTargetPrediction databases. Pain-related targets were selected in the OMIM, Gene- Cards, and DrugBank databases. These targets were intersected to obtain potential analgesic targets. The analgesic targets were imported into the STRING and DAVID databases for protein-protein interaction (PPI), gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Cytoscape software (V3.7.1) was used to construct an active component-intersection network. Finally, the key components were docked with the core targets. The analgesic mechanism of CQQNC was verified by RAW264.7 cell experiment. RESULTS: 30 active CQQNC components, 617 corresponding targets, and 3,214 pain-related target genes were found. The main active components were quercetin, kaempferol, and chenodeoxycholic acid etc. The key targets were ALB, AKT1, TNF, IL6, TP53, IL1B, and SRC. CQQNC can exert an analgesic effect through PI3K-Akt, MAPK signaling pathways, etc. Molecular docking showed that these active components had good binding activities with key targets. The results of in vitro experiments showed that CQQNC could exert antiinflammatory and analgesic effects through MAPK/AKT/NF-kB signaling pathways. CONCLUSION: CQQNC exerts pain control through inhibiting MAPK/AKT/NF-kB signaling pathways.

Systematic pan-cancer analyses of the potential function of the Golgi scaffold protein PAQR3.

Progesterone and AdipoQ Receptor 3 (PAQR3) is a member of the AdipoQ receptor. Our previous studies have found that PAQR3 plays a role as a candidate inhibitor in cardiac adenocarcinoma, breast cancer, gastric cancer and colorectal cancer, but the systematic analysis of PAQR3 in tumors is currently lacking. The objective of this study was to investigate the prognostic and therapeutic value of PAQR3 in 31 tumors. Through the analysis of TCGA, UALCAN, GEO, GEPIA2, TIMER, Kaplan-Meier plotter, TISIDB and other databases, it was found that the expression level of PAQR3 changed significantly in different tumor types, and the expression level of Neuroblastoma was very high. And the level of Prostate adenocarcinoma is low. In addition, the expression level of PAQR3 in Cholangiocarcinoma, Esophageal carcinoma, Head and neck squamous carcinoma, Liver Hepatocellular Carcinoma, Lung Adenocarcinoma and Lung squamous cell carcinoma was significantly higher than that in normal tissues. However, the expression level of PAQR3 in Breast Cancer, Kidney Renal Clear Cell Carcinoma, Kidney renal papillary cell carcinoma, Prostate Adenocarcinoma, Rectum Adenocarcinoma, Thyroid Cancer and Uterine Corpus Endometrial Carcinoma was lower than that in normal tissues. Subsequently, we explored the value of PAQR3 as a prognostic indicator of cancer. In Acute Myeloid Leukemia, Lower-grade Glioma and Glioblastoma, Pediatric Low-grade Gliomas, Kidney Chromophobe, and Thyroid Cancer, PAQR3 expression was positively correlated with OS and DSS, while in Rectum Adenocarcinoma, PAQR3 expression was negatively correlated with OS. PAQR3 high expression group Lower-grade Glioma and Glioblastoma, Pediatric Low-grade Gliomas, Uveal Melanoma, Kidney Chromophobe and DFI were positively correlated. PAQR3 can be used as a risk factor for the prognosis of multiple tumors. Then, we discussed the correlation between PAQR3 and immunology, and found that PAQR3 has a wide range of mutations in various tumor types, the most common mutation type is missense mutation, and common mutation types also include amplification, depth deletion, splicing, truncation and structural variation. Among the tumor samples with PAQR3 alterations, mutation occurred in all tumor samples except prostate adenocarcinoma and adrenal cortical carcinoma, head and neck squamous cell carcinoma, brain low-grade glioma, and kidney clear cell carcinoma, while esophageal adenocarcinoma had the highest total alteration frequency. PAQR3 was strongly associated with CNV in 18 tumors, particularly in Ovarian cancer, Lung squamous cell carcinoma, and Adenoid cystic carcinoma. On the other hand, PAQR3 has a higher SNV frequency in Uterine Corpus Endometrial Carcinoma, Skin Cutaneous Melanoma and Lung Adenocarcinoma, among which Uterine Corpus Endometrial Carcinoma has the highest SNV frequency. These results showed that PAQR3 expression levels were significantly correlated with tumor mutation load, microsatellite instability, neoantigens, and purity. In summary, PAQR3 can affect the tumor microenvironment and has potential for chemotherapy. Finally, we investigated the role of PAQR3 in tumor resistance and found that the expression of PAQR3 affects the efficacy of multiple chemotherapy drugs. Based on these studies, we found that PAQR3 plays an important role in cancer and has potential in tumor diagnosis and prognosis.

Suppression of neutrophil extracellular traps is responsible for the amelioration of chemotherapeutic intestinal injury by the natural compound PEITC.

Intestinal injury is one of the most debilitating side effects of many chemotherapeutic agents, such as irinotecan hydrochloride (CPT-11). Accumulating evidence indicates that neutrophil extracellular traps (NETs) play a critical role in the symptoms of ischemia and inflammation related to chemotherapy. The present study investigated the effects and possible mechanisms of phenethyl isothiocyanate (PEITC) in inhibiting NETs and alleviating chemotherapeutic intestinal injury. CPT-11 induced robust neutrophil activation, as evidenced by increased NETs release, intestinal ischemia, and mRNA expression of inflammatory factors. PEITC prolonged the clotting time of chemotherapeutic mice, improved the intestinal microcirculation, inhibited the expression of inflammatory factors, and protected the tight junctions of the intestinal epithelium. Both in vivo and in vitro experiments revealed that PEITC directly suppresses CPT-11-induced NETs damage to intestinal cells, resulting in significant attenuation of epithelial injury. These results suggest that PEITC may be a novel agent to relieve chemotherapeutic intestinal injury via inhibition of NETs.