Common Chemotherapeutic Drugs Research Articles

Activation of SIRT3 by Tanshinone IIA ameliorates renal fibrosis by suppressing the TGF-β/TSP-1 pathway and attenuating oxidative stress.

Although doxorubicin (DOX) is a common chemotherapeutic drug, the serious nephrotoxicity caused by DOX-induced renal fibrosis remains a considerable clinical problem. Tanshinone IIA (Tan IIA), a compound extracted from Salvia miltiorrhiza, has been reported to have an anti-fibrotic effect. Therefore, this study investigated the molecular pathway whereby Tan IIA protects the kidneys from DOX administration. DOX (3mg/kg body weight) was intraperitoneally administered every 3 d for a total of 7 injections (cumulative dose of 21mg/kg) to induce nephrotoxicity. Then, Tan IIA (5 or 10mg/kg/d) was administered by intraperitoneal injection for 28 d. In an in vitro study, 293T cells were cultured and treated with DOX and Tan IIA for 24h. Tan IIA reduced the blood urea nitrogen levels elevated by DOX while increasing superoxide dismutase activity, down-regulating reactive oxygen species, ameliorating renal-tubule thickening, and rescuing mitochondrial morphology. Additionally, Tan IIA reduced the renal collagen deposition, increased ATP production and complex-I activity, down-regulated transforming growth factor-β1 (TGF-β1) and thrombospondin-1 (TSP-1), and up-regulated sirtuin 3 (SIRT3). Tan IIA significantly increased cell viability. Additionally, RNA interference was employed to silence the expression of SIRT3, which eliminated the effect of Tan IIA in suppressing the expression of TGF-β1 and TSP-1. In conclusion, Tan IIA ameliorated DOX-induced nephrotoxicity by attenuating oxidative injury and fibrosis. The Tan IIA-induced rescue of mitochondrial morphology and function while alleviating renal fibrosis may be associated with the activation of SIRT3 to suppress the TGF-β/TSP-1 pathway.

Prognostic aging gene-based score for colorectal cancer: unveiling links to drug resistance, mutation burden, and personalized treatment strategies

ObjectiveColorectal cancer (CRC) is characterized by high incidence and mortality rates worldwide. In this study, we present a novel aging-related gene-based risk scoring system (Aging score) as a predictive tool for CRC prognosis. Method: We identified prognostic aging-related genes using univariate Cox regression analysis, revealing key biological processes in CRC progression. We then constructed a robust prognostic model using LASSO and multivariate Cox regression analyses, including four critical genes: CAV1, FOXM1, MAD2L1, and WT1. Result: The Aging score demonstrated high prognostic performance across the training, testing, and entire TCGA-CRC datasets, proving its reliability. High-risk patients identified by the Aging score had significantly shorter overall survival times than low-risk patients, indicating its potential for patient stratification and personalized treatment. The Aging score remained an independent prognostic factor compared to age, gender, and tumor stage. Additionally, the score was linked to tumor mutation burden and microsatellite instability, indicators of immune checkpoint inhibitor response. High-risk patients also showed higher estimated IC50 values for common chemotherapeutic drugs, suggesting possible treatment resistance. Conclusion: Our findings highlight the Aging score's potential to enhance clinical decision-making and pave the way for personalized CRC management.

In Vitro and In Vivo Effects of Melatonin-Containing Combinations in Human Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis and high mortality rates. Therefore, it is necessary to identify new targets and therapeutic strategies to improve the prognosis of patients with PDAC. Integrative therapies are increasingly being used to boost the efficacy of the known anticancer therapeutic approaches. Hence, this study aimed to evaluate the effects of a novel combination of different potential anticancer molecules, melatonin (MLT), cannabidiol (CBD), and oxygen-ozone (O2/O3) to treat PDAC using in vitro and in vivo models of human PDAC. The effect of this combination was investigated in combination with gemcitabine (GEM), the most common chemotherapeutic drug used for PDAC treatment. The combination of MLT + CBD + O2/O3 was more effective than the individual treatments in inhibiting PDAC cell viability and proliferation, inducing cell death, and modulating the RAS pathway protein levels. Moreover, different combinations of treatments reduced tumor mass in the PDAC mouse model, thus promoting the effect of GEM. In conclusion, a mixture of MLT + CBD + O2/O3 couldserve as a potential adjuvant therapeutic strategy for PDAC.

Targeting HMGCS1 restores chemotherapy sensitivity in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a common hematological malignancy with overall poor prognosis. Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory (RR) AML patients. Through clinical specimens, animal models and cell-level studies, we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation, increase chemotherapy sensitivity and improve the occurrence and development of AML. Here, we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival (OS). Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity, while stable overexpression of HMGCS1 had the opposite effects. Mechanistically, we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase (MAPK) pathway activity, while overexpression of HMGCS1 could remarkably enhance the pathway. U0126, a MEK1 inhibitor, offset the effects of HMGCS1 overexpression, indicating that HMGCS1 promotes RR AML through the MAPK pathway. Further, we verified that hymeglusin, a specific inhibitor of HMGCS1, decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients. Furthermore, combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin (ADR) had synergistic toxic effects on AML cells. Our study demonstrates the important role of HMGCS1 in AML, and targeting this protein is promising for the treatment of RR AML.

Parecoxib and 5-Fluorouracil Synergistically Inhibit EMT and Subsequent Metastasis in Colorectal Cancer by Targeting PI3K/Akt/NF-κB Signaling.

Colorectal cancer is one of the most common causes of cancer mortality worldwide, and innovative drugs for the treatment of colorectal cancer are continually being developed. 5-Fluorouracil (5-FU) is a common clinical chemotherapeutic drug. Acquired resistance to 5-FU is a clinical challenge in colorectal cancer treatment. Parecoxib is a selective COX-2-specific inhibitor that was demonstrated to inhibit metastasis in colorectal cancers in our previous study. This study aimed to investigate the synergistic antimetastatic activities of parecoxib to 5-FU in human colorectal cancer cells and determine the underlying mechanisms. Parecoxib and 5-FU synergistically suppressed metastasis in colorectal cancer cells. Treatment with the parecoxib/5-FU combination induced an increase in E-cadherin and decrease in β-catenin expression. The parecoxib/5-FU combination inhibited MMP-9 activity, and the NF-κB pathway was suppressed as well. Mechanistic analysis denoted that the parecoxib/5-FU combination hindered the essential molecules of the PI3K/Akt route to obstruct metastatic colorectal cancer. Furthermore, the parecoxib/5-FU combination could inhibit reactive oxygen species. Our work showed the antimetastatic capacity of the parecoxib/5-FU combination for treating colorectal cancers via the targeting of the PI3K/Akt/NF-κB pathway.

Exosomes Mediate the Production of Oxaliplatin Resistance and Affect Biological Behaviors of Colon Cancer Cell Lines.

Colon cancer has high mortality rate which making it one of the leading causes of cancer deaths. Oxaliplatin is a common chemotherapeutic drug, but it has disadvantages such as drug resistance. The purpose of this study is to explore the mechanism of exosomes in the resistance of oxaliplatin and verify whether elemene and STAT3 inhibitors reverse the resistance to oxaliplatin. Related cell line models were constructed and the proliferation, migration, invasion, apoptosis and resistance to oxaliplatin were evaluated for all three cells of HCT116/L, sensitive cell HCT116 and HCT116+HCT116/L-exosomes (HCT116-exo). It was to explore probable signaling pathways and mechanisms by Western blotting. HCT116-exo drug-resistant chimeric cells showed greater capacity for proliferation, migration and invasion than HCT116 sensitive cells. After the above cells were treated with oxaliplatin, the apoptosis rate of chimeric drug-resistant cells HCT116-exo and its IC50 increased compared with the sensitive cells HCT116. The proliferation, invasion and migration of cells treated with STAT3 inhibitor or β-elemene combined with oxaliplatin reduced compared with those treated with oxaliplatin or β-elemene alone. The STAT3 inhibitor or β-elemene in combination with oxaliplatin increased the rate of apoptosis relative to oxaliplatin or β-elemene alone. Drug-resistant cell exosomes could promote the EMT process, related to the participation of FGFR4, SHMT2 and STAT3 inhibitors. Drug-resistant cell exosomes could induce resistance, and improve the capacity of colon cancer towards proliferate, invade, migrate and promote the EMT process. The β-elemene combined with oxaliplatin could reverse the above results which might be related to the STAT3 pathway and EMT pathway in colon cancer.

Enhancing Chemotherapy Efficacy: Investigating the Synergistic Impact of Paclitaxel and cd73 Gene Suppression on Breast Cancer Cell Proliferation and Migration.

Background Enhancing chemotherapy efficacy is crucial in breast cancer treatment. This study examines the synergistic effects of paclitaxel, a common chemotherapeutic drug, andCluster of differentiation 73(cd73) gene suppression via siRNA on MDA-MB-231 breast cancer cells. Methods MDA-MB-231 cells were transfected with CD73 siRNA and treated with paclitaxel.Cell viability, apoptosis, and migration wereassessed by using MTT assays, Annexin V-FITC/PI staining, and wound healing assays, respectively, with flow cytometry analyzing cell cycle distribution. Results The combination of CD73 siRNA and paclitaxel significantly reduced cell viability, lowering paclitaxel's IC50 from 14.73 μg/mL to 8.471 μg/mL, indicating enhanced drug sensitivity. Apoptosis rates increased with the combination treatment, while cell migration was significantly inhibited. Flow cytometry revealed cell cycle arrest in the Sub-G1 and G2-M phases. Conclusion These findings suggest that cd73 gene suppression enhances paclitaxel's cytotoxic effects, promoting apoptosis and inhibiting cell migration in MDA-MB-231 breast cancer cell line. This combined strategy shows promise for improving breast cancer treatment outcomes by increasing the efficacy of existing chemotherapeutic regimens, warranting further research to explore its potential clinical applications and effectiveness in other breast cancer cell lines and models.

Actinomycin D and bortezomib disrupt protein homeostasis in Wilms tumor.

Wilms tumor is the most common kidney cancer in children, and diffusely anaplastic Wilms tumor is the most chemoresistant histological subtype. Here we explore how Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal RNA biogenesis. Using ribosome profiling, protein arrays, and a genome-wide knockout screen, we describe how actinomycin D disrupts protein homeostasis and blocks cell cycle progression. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Furthermore, the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment by inducing apoptosis both in vitro and in vivo. Lastly, we show that increased levels of proteasome components are associated with anaplastic histology and with worse prognosis in non-anaplastic Wilms tumor. In sum, maintaining protein homeostasis is critical for Wilms tumor proliferation, and it can be therapeutically disrupted by blocking protein synthesis or turnover.

Identification of the biological functions and chemo-therapeutic responses of ITGB superfamily in ovarian cancer

BackgroundPatients with ovarian cancer (OC) tend to face a poor prognosis due to a lack of typical symptoms and a high rate of recurrence and chemo-resistance. Therefore, identifying representative and reliable biomarkers for early diagnosis and prediction of chemo-therapeutic responses is vital for improving the prognosis of OC.MethodsExpression levels, IHC staining, and subcellular distribution of eight ITGBs were analyzed using The Cancer Genome Atlas (TCGA)-Ovarian Serous Cystadenocarcinoma (OV) database, GEO DataSets, and the HPA website. PrognoScan and Univariate Cox were used for prognostic analysis. TIDE database, TIMER database, and GSCA database were used to analyze the correlation between immune functions and ITGBs. Consensus clustering analysis was performed to subtype OC patients in the TCGA database. LASSO regression was used to construct the predictive model. The Cytoscape software was used for identifying hub genes. The ‘pRRophetic’ R package was applied to predict chemo-therapeutic responses of ITGBs.ResultsITGBs were upregulated in OC tissues except ITGB1 and ITGB3. High expression of ITGBs correlated with an unfavorable prognosis of OC except ITGB2. In OC, there was a strong correlation between immune responses and ITGB2, 6, and 7. In addition, the expression matrix of eight ITGBs divided the TCGA-OV database into two subgroups. Subgroup A showed upregulation of eight ITGBs. The predictive model distinguishes OC patients from favorable prognosis to poor prognosis. Chemo-therapeutic responses showed that ITGBs were able to predict responses of common chemo-therapeutic drugs for patients with OC.ConclusionsThis article provides evidence for predicting prognosis, immuno-, and chemo-therapeutic responses of ITGBs in OC and reveals related biological functions of ITGBs in OC.

HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.

Cancer, a chronic disease characterized by uncontrolled cell development, kills millions of people globally. The WHO reported over 10 million cancer deaths in 2020. Anticancer medications destroy healthy and malignant cells. Cancer treatment induces neuropathy. Anticancer drugs cause harm to spinal cord, brain, and peripheral nerve somatosensory neurons, causing chemotherapy-induced neuropathic pain. The chemotherapy-induced mechanisms underlying neuropathic pain are not fully understood. However, neuroinflammation has been identified as one of the various pathways associated with the onset of chemotherapy-induced neuropathic pain. The neuroinflammatory processes may exhibit varying characteristics based on the specific type of anticancer treatment delivered. Neuroinflammatory characteristics have been observed in the spinal cord, where microglia and astrocytes have a significant impact on the development of chemotherapy-induced peripheral neuropathy. The patient's quality of life might be affected by sensory deprivation, loss of consciousness, paralysis, and severe disability. High cancer rates and ineffective treatments are associated with this disease. Recently, histone deacetylases have become a novel treatment target for chemotherapy-induced neuropathic pain. Chemotherapy-induced neuropathic pain may be treated with histone deacetylase inhibitors. Histone deacetylase inhibitors may be a promising therapeutic treatment for chemotherapy-induced neuropathic pain. Common chemotherapeutic drugs, mechanisms, therapeutic treatments for neuropathic pain, and histone deacetylase and its inhibitors in chemotherapy-induced neuropathic pain are covered in this paper. We propose that histone deacetylase inhibitors may treat several aspects of chemotherapy-induced neuropathic pain, and identifying these inhibitors as potentially unique treatments is crucial to the development of various chemotherapeutic combination treatments.

An inflammation-related subtype classification for analyzing tumor microenvironment and clinical prognosis in colorectal cancer.

The inflammatory response plays an essential role in the tumor microenvironment (TME) of colorectal cancer (CRC) by modulating tumor growth, progression, and response to therapy through the recruitment of immune cells, production of cytokines, and activation of signaling pathways. However, the molecular subtypes and risk score prognostic model based on inflammatory response remain to be further explored. Inflammation-related genes were collected from the molecular signature database and molecular subtypes were identified using nonnegative matrix factorization based on the TCGA cohort. We compared the clinicopathological features, immune infiltration, somatic mutation profile, survival prognosis, and drug sensitivity between the subtypes. The risk score model was developed using LASSO and multivariate Cox regression in the TCGA cohort. The above results were independently validated in the GEO cohort. Moreover, we explored the biological functions of the hub gene, receptor interacting protein kinase 2 (RIPK2), leveraging proteomics data, in vivo, and in vitro experiments. We identified two inflammation-related subtypes (inflammation-low and inflammation-high) and have excellent internal consistency and stability. Inflammation-high subtype showed higher immune cell infiltration and increased sensitivity to common chemotherapeutic drugs, while inflammation-low subtype may be more suitable for immunotherapy. Besides, the two subtypes differ significantly in pathway enrichment and biological functions. In addition, the 11-gene signature prognostic model constructed from inflammation-related genes showed strong prognostic assessment power and could serve as a novel prognostic marker to predict the survival of CRC patients. Finally, RIPK2 plays a crucial role in promoting malignant proliferation of CRC cell validated by experiment. This study provides new insights into the heterogeneity of CRC and provides novel opportunities for treatment development and clinical decision making.

Nanoparticle-functionalized acrylic bone cement for local therapeutic delivery to spine metastases

Aim: Polymethylmethacrylate bone cement is often used to reconstruct critical-sized defects generated by the surgical resection of spinal metastases. Residual tumor cells after a resection can drive recurrence and destabilization. Doxorubicin (DOX) is a common chemotherapeutic drug with unwanted side-effects when administered systemically. Mesoporous silica nanoparticles (NPs) are gaining attention for targeted drug delivery to bypass the negative side effects associated with systemic drug administration. An NP-functionalized cement was developed for the local release of DOX and its ability to suppress cancer cells was tested. Methods: DOX was loaded onto NPs which were then mixed into the cement. Static contact angles were measured. Drug release profiles were obtained over a period of 4 weeks. Cement constructs were incubated with two-dimensional (2D) cultures of human bone-marrow derived mesenchymal stem cells and human osteoblasts, as well as 2D and three-dimensional (3D) cultures of breast and prostate cancer cell lines. Cell metabolic activity and viability were evaluated. Cell migration and spheroid growth of cancer cell lines were assessed in collagen-coated spheroid cultures. Results: NPs were homogenously dispersed and did not alter the mechanical strength nor the wettability of the cement. A sustained DOX release profile was achieved with the addition of NPs to the bone cement. The release profile of DOX from NP cement may be modified by varying the amount of the drug loaded onto the NPs and the proportion of NPs in the cement. Cancer cells treated with the cement constructs showed a dose- and time-dependent inhibition, with minimal toxicity against healthy cells. Cancer cell migration and spheroid growth were impaired in 3D culture. Conclusions: NPs were shown to be essential for sustained DOX release from bone cement. DOX-loaded NP cement can inhibit cancer cells and impair their migration, with strong potential for in vivo translation studies.

Efficacy and safety of raltitrexed-eluting CalliSpheres® bead transarterial chemoembolization in patients with intermediate-stage hepatocellular carcinoma: a single-arm, prospective study.

The most common loadable chemotherapeutic drugs in drug-eluting bead transarterial chemoembolization (DEB-TACE) include doxorubicin, epirubicin, etc. CalliSpheres® beads have exhibited efficient loadability and eluting characteristics for raltitrexed as well as in vitro and animal experiments. However, the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage hepatocellular carcinoma (HCC) remain unclear. To assess the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage HCC. The study was conducted as a single-arm prospective study. This study was a prospective, single-arm trial conducted between June 2019 and June 2022. CalliSpheres® beads loaded with raltitrexed were used in the DEB-TACE procedure. The follow-up lasted for at least 1 year or until death. The primary endpoint was overall survival (OS), and the secondary endpoints were time to progression (TTP), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). The 6-month ORR and disease control rates were 90.1% and 93.8%, respectively. The median OS was 33.0 months. The 1-, 2-, and 3-year survival rates were 95.1%, 82.1%, and 43.6%, respectively. Child-Pugh class and bilobar disease occurrence were identified as independent OS predictors. The median TTP and PFS were 22.7 and 19.8 months, respectively. Eleven (11.5%) patients experienced at least one grade 3 AE, and serious AEs were reported in five participants (5.2%). No patient experienced grade 4 or 5 AEs. Raltitrexed-loaded DEB-TACE is feasible, safe, and effective in patients with intermediate-stage HCC. This trial was registered at www.chictr.org.cn under the identifier: 1900024097 on 25 June 2019.

Identification of basement membrane-related signatures for estimating prognosis, immune infiltration landscape and drug candidates in pancreatic adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a frequent digestive system cancer, which has high mortality and bad outcome. However, the role of basement membrane (BM)-related gene in assessing patient's outcome, microenvironment and treatment response remain unclear. Methods: Basement membrane (BM)-associated genes were detected by univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses using data from the TCGA databases. A risk score system was constructed to distinguish patients in the high- and low-risk groups. Prognostic gene distribution in various immune cell forms was explored through scRNA-seq. Immune cell infiltration was assessed using CIBERSORT and ESTIMATE. The IC50 of common chemotherapeutic drugs and useful molecule compounds were evaluated. The mRNA and protein expression of important signatures were validated utilizing GEPIA and HPA databases. Results: Compared to low risk PAAD patients, PAAD patients with high risk showed a significant much worse overall survival (OS). Risk score of BM-associated genes could estimate patient outcome well, and areas under the curve (AUC) of receiver operating characteristic (ROC) survival curve were 0.76, 0.85, and 0.85 at 1-, 3-, and 5-year. Clinical impact curve (CIC) curve demonstrated the clinical importance of risk score. scRNA-seq revealed that BM-related genes were mainly distributed in malignant cells. Significant variations existed in the immune microenvironment, immune checkpoint expression and chemotherapy response between the studied groups. Furthermore, the mRNA expression levels of FAM83A, LY6D, MET, MUC16, MYEOV, and WNT7A were elevated in PAAD tissues, while the protein expression patterns of LY6D, MET, MUC16, and WNT7A were higher in tumor sample. RO-90-7501, Scriptaid, TG-101348, XMD-892, and XMD-1150 may be valuable small molecule drugs to treat PAAD. Conclusions: In conclusion, we develop a novel BM-related gene signature provide new insights and targets for the diagnosis, outcome estimation, candidate drugs and therapy management of PAAD patients.

Molecular Classification of HNSCC Based on Inflammatory Response-Related Genes - Integrated Single-Cell and Bulk RNA-Seq Analysis.

Tumor cells, inflammatory cells, and chemical factors collaboratively orchestrate a sophisticated signaling network, culminating in the formation of the inflammatory tumor microenvironment (TME). The present study sought to explore the nature of the inflammatory response in HNSCC and to decipher its influence on immunotherapeutic. A thorough analysis was performed utilizing the TCGA cohort along with two GEO cohorts. Unsupervised clustering of 200 inflammatory response-related genes (IRGs) was applied using the k-means algorithm to explore the heterogeneity of HNSCC. Additionally, a prognostic signature based on IRGs genes was constructed using Lasso regression. Meanwhiles, the expression of IRGs were identified in tumors and paracancerous tissues at the single-cell level. The crosstalk between IRGs was explored using CellChat and the patterns of incoming and outgoing signals were identified. Finally, qPCR was used to verify the expression of hub genes. There were significant differences in immune-cell function and immune-cell infiltration among three inflammatory response clusters. Additionally, we also constructed a prognostic model which could predicted the responses of common chemotherapeutic drugs and immunotherapy. Furthermore, qPCR and sc-RNA seq corroborated that the expression profiles of the prognostic genes were largely in alignment with the findings from the bioinformatics analysis. Ultimately, the molecular docking demonstrated favorable binding affinities between the pivotal gene-SCC7 and four chemotherapeutic drugs. This research has uniquely shed light on the intricate connection between the inflammatory response profiles and the immune infiltration patterns in HNSCC.

Integration of single-cell RNA-seq and bulk RNA-seq to construct liver hepatocellular carcinoma stem cell signatures to explore their impact on patient prognosis and treatment.

Liver hepatocellular carcinoma (LIHC) is a prevalent form of primary liver cancer. Research has demonstrated the contribution of tumor stem cells in facilitating tumor recurrence, metastasis, and treatment resistance. Despite this, there remains a lack of established cancer stem cells (CSCs)-associated genes signatures for effectively predicting the prognosis and guiding the treatment strategies for patients diagnosed with LIHC. The single-cell RNA sequencing (scRNA-seq) and bulk RNA transcriptome data were obtained based on public datasets and computerized firstly using CytoTRACE package and One Class Linear Regression (OCLR) algorithm to evaluate stemness level, respectively. Then, we explored the association of stemness indicators (CytoTRACE score and stemness index, mRNAsi) with survival outcomes and clinical characteristics by combining clinical information and survival analyses. Subsequently, weighted co-expression network analysis (WGCNA) and Cox were applied to assess mRNAsi-related genes in bulk LIHC data and construct a prognostic model for LIHC patients. Single-sample gene-set enrichment analysis (ssGSEA), Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Tumor Immune Estimation Resource (TIMER) analysis were employed for immune infiltration assessment. Finally, the potential immunotherapeutic response was predicted by the Tumor Immune Dysfunction and Exclusion (TIDE), and the tumor mutation burden (TMB). Additionally, pRRophetic package was applied to evaluate the sensitivity of high and low-risk groups to common chemotherapeutic drugs. A total of four genes (including STIP1, H2AFZ, BRIX1, and TUBB) associated with stemness score (CytoTRACE score and mRNAsi) were identified and constructed a risk model that could predict prognosis in LIHC patients. It was observed that high stemness cells occurred predominantly in the late stages of LIHC and that poor overall survival in LIHC patients was also associated with high mRNAsi scores. In addition, pathway analysis confirmed the biological uniqueness of the two risk groups. Personalized treatment predictions suggest that patients with a low risk benefited more from immunotherapy, while those with a high risk group may be conducive to chemotherapeutic drugs. The current study developed a novel prognostic risk signature with genes related to CSCs, which provides novel ideas for the diagnosis, prognosis and treatment of LIHC.

A Research on Clinical Pharmacists' Assessment of Drug-Related Problems in Patients with Chronic Kidney Disease

The aim of the study is to Spirulina protective effects against acute Fenitrothion-induced toxicity in rats. The objective of a present investigation has been to determine if Spirulina could protect male Wistar albino rats from the toxic effects of Fenitrothion by acting as an antioxidant and hepato-nephroprotector. The toxic effects of DLM are significantly influenced by oxidative stress. In numerous earlier interventions, antioxidants are useful in reducing DLM-induced toxicity. Spirulina is a strong antioxidant that has the potential to lessen the effects of numerous common chemotherapeutic drugs and insecticides. It is evident from the current study that DLM exposure caused variable changes in serum biochemical indicators, levels of lipid peroxidation, and the inhibition of antioxidant enzyme activity. In terms of biochemical changes in blood and tissues, antioxidant enzyme activity, and oxidative stress, AP pre-exposure offered almost full protection.

Docetaxel Inhibits Epithelial-Mesenchymal Transition in Human Mammary Cells.

Epithelial-mesenchymal transition (EMT) is a reversible and dynamic biological process in which epithelial cells acquire mesenchymal characteristics including enhanced stemness and migratory ability. EMT can facilitate cancer metastasis and is a known driver of cellular resistance to common chemotherapeutic drugs, such as docetaxel. Current chemotherapeutic practices such as docetaxel treatment can promote EMT and increase the chance of tumor recurrence and resistance, calling for new approaches in cancer treatment. Here we show that prolonged docetaxel treatment at a sub-IC50 concentration inhibits EMT in immortalized human mammary epithelial (HMLE) cells. Using immunofluorescence, flow cytometry, and bulk transcriptomic sequencing to assess EMT progression, we analyzed a range of cellular markers of EMT in docetaxel-treated cells and observed an upregulation of epithelial markers and downregulation of mesenchymal markers in the presence of docetaxel. This finding suggests that docetaxel may have clinical applications not only as a cytotoxic drug but also as an inhibitor of EMT-driven metastasis and multidrug resistance depending on the concentration of its use.

Caffeine-folic acid-loaded-chitosan nanoparticles combined with methotrexate as a novel HepG2 immunotherapy targeting adenosine A2A receptor downstream cascade

BackgroundMethotrexate (MTX) is a common chemotherapeutic drug that inhibits DNA synthesis and induces apoptosis. Treatment with MTX increased CD73 expression, which leads to higher levels of extracellular adenosine. Adenosine levels are also high in the tumor microenvironment through Cancer cells metabolism. That promotes the survival of cancer cells and contributes to tumor immune evasion through the Adenosine 2a Receptor. A2A receptor antagonists are an emerging class of agents that treat cancers by enhancing immunotherapy, both as monotherapy and in combination with other therapeutic agents. Caffeine is an adenosine receptor antagonist. Herein, we demonstrate the ability of a novel well prepared and characterized nano formula CAF-FA-CS-NPs (D4) for A2aR blockade when combination with MTX to improve its antitumor efficacy by enhancing the immune system and eliminating immune suppression.MethodsCAF-FA-CS-NPs (D4) were prepared and characterized for particle size, loading efficiency, and release profile. Molecular docking was used to validate the binding affinity of caffeine and folic acid to A2A receptor. The effects of the nano formula were evaluated on human liver cancer cells (HepG2), breast cancer cells (MCF-7), and MDA-MB-231, as well as normal human cells (WI-38). Different combination ratios of MTX and D4 were studied to identify the optimal combination for further genetic studies.ResultsMolecular docking results validated that caffeine and folic acid have binding affinity to A2A receptor. The CS-NPs were successfully prepared using ionic gelation method, with caffeine and folic acid being loaded and conjugated to the nanoparticles through electrostatic interactions. The CAF loading capacity in D4 was 77.9 ± 4.37% with an encapsulation efficiency of 98.5 ± 0.37. The particle size was optimized through ratio variations. The resulting nanoparticles were fully characterized. The results showed that (D4) had antioxidant activity and cytotoxicity against different cancer cells. The combination of D4 with MTX (IC50 D4 + 0.5 IC50 MTX) resulted in the downregulation of Bcl-2, FOXP3, CD39, and CD73 gene expression levels and upregulation of Bax and A2AR gene expression levels in HepG2 cells.ConclusionsThis study suggests that CAF-FA-CS-NPs (D4) in combination with MTX may be a promising candidate for cancer immunotherapy, by inhibiting A2aR signaling and leading to improved immune activation and anti-tumor activity of MTX.

Three molecular subtypes and a five-gene signature for hepatocellular carcinoma based on m7G-related classification.

The current research investigated the heterogeneity of hepatocellular carcinoma (HCC) based on the expression of N7-methylguanosine (m7G)-related genes as a classification model and developed a risk model predictive of HCC prognosis, key pathological behaviors and molecular events of HCC. The RNA sequencing data of HCC were extracted from The Cancer Genome Atlas (TCGA)-live cancer (LIHC) database, hepatocellular carcinoman database (HCCDB) and Gene Expression Omnibus database, respectively. According to the expression level of 29 m7G-related genes, a consensus clustering analysis was conducted. The least absolute shrinkage and selection operator (LASSO) regression analysis and COX regression algorithm were applied to create a risk prediction model based on normalized expression of five characteristic genes weighted by coefficients. Tumor microenvironment (TME) analysis was performed using the MCP-Counter, TIMER, CIBERSORT and ESTIMATE algorithms. The Tumor Immune Dysfunction and Exclusion algorithm was applied to assess the responses to immunotherapy in different clusters and risk groups. In addition, patient sensitivity to common chemotherapeutic drugs was determined by the biochemical half-maximal inhibitory concentration using the R package pRRophetic. Three molecular subtypes of HCC were defined based on the expression level of m7G-associated genes, each of which had its specific survival rate, genomic variation status, TME status and immunotherapy response. In addition, drug sensitivity analysis showed that the C1 subtype was more sensitive to a number of conventional oncolytic drugs (including paclitaxel, imatinib, CGP-082996, pyrimethamine, salubrinal and vinorelbine). The current five-gene risk prediction model accurately predicted HCC prognosis and revealed the degree of somatic mutations, immune microenvironment status and specific biological events. In this study, three heterogeneous molecular subtypes of HCC were defined based on m7G-related genes as a classification model, and a five-gene risk prediction model was created for predicting HCC prognosis, providing a potential assessment tool for understanding the genomic variation, immune microenvironment status and key pathological mechanisms during HCC development.