ABSTRACT
Drug-induced liver injury (DILI) is one of the most frequently adverse reactions in clinical drug use, usually caused by drugs or herbal compounds. Compared with other populations, cancer patients are more prone to abnormal liver function due to primary or secondary liver malignant tumor, radiation-induced liver injury and other reasons, making potential adverse reactions from liver damage caused by anticancer drugs of particular concernduring clinical treatment process. In recent years, the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has changed the treatment status of a series of solid malignant tumors. Unfortunately, the increasing incidence of hepatotoxicitylimits the clinical application of EGFR-TKIs. The mechanisms of liver injury caused by EGFR-TKIs were complex. Despite more than a decade of research, other than direct damage to hepatocytes caused by inhibition of cellular DNA synthesis and resulting in hepatocyte necrosis, the rest of the specific mechanisms remain unclear, and few effective solutions are available. This review focuses on the clinical feature, incidence rates and the recent advances on the discovery of mechanism of hepatotoxicity in EGFR-TKIs, as well as rechallenge and therapeutic strategies underlying hepatotoxicity of EGFR-TKIs.
ABSTRACT
The clinical application of polymyxin B (PMB) is limited by its nephrotoxic effects, making the reduction of PMB-induced nephrotoxicity has become a pressing concern for clinicians. Tetrahydrocurcumin (THC), known for its beneficial characteristics in biological functions, presents an attractive option for intervention therapy to mitigate PMB-induced nephrotoxicity. However, the underlying mechanism of how THC mitigates PMB-induced nephrotoxicity is still poorly understood. Here, we first evaluated the potential of THC intervention therapy to mitigate PMB-induced nephrotoxicity in an in vitro model of PMB-induced cell injury. Moreover, we demonstrated that THC effectively protected HK-2 cells from PMB-induced apoptosis by using cell counting kit-8 and flow cytometry assay. THC could also suppress PMB-induced endoplasmic reticulum (ER) stress via PERK/eIF2α/ATF4/CHOP pathway. In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB-induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB-induced nephrotoxicity by inhibiting the ER stress-mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB-induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment.
ABSTRACT
Following the publication of this article, an interested reader drew to the authors' attention that the flow cytometric (FCM) plots in Fig. 2A on p. 2278 showing the 'Dasatinib' and 'CA4' experiments were duplicates of each other. After having reexamined their original data, and due to the overall similarity of the data, the authors have realized that these data were inadvertently assembled incorrectly in the figure. They realize that they also made a further mistake regarding the writing of the ratios of mitochondrial membranedepolarized HO8910 cells for these FCM plots (essentially, these were written the wrong way around): The percentage of mitochondrial membranedepolarized HO8910 cells should have been written as 22.50% for the dasatinibtreated cells (the centreleft FCM plot) and 15.71% for the CA4treated cells (centreright plot). A revised version of Fig. 2 now showing alternative data for the FCM experiments shown in Fig. 2A, is shown on the next page. Note that the errors made in terms of assembling the data in Fig. 2A did not greatly affect either the results or the conclusions reported in this paper, and all the authors agree with the publication of this corrigendum. The authors regret that these errors went unnoticed prior to the publication of their article, and are grateful to the Editor of Oncology Reports for granting them this opportunity to publish a corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [Oncology Reports 29: 22752282, 2013; DOI: 10.3892/or.2013.2405].
ABSTRACT
5-Aminosalicylic acid (5-ASA) is a first-line agent in both remission and maintenance therapy for ulcerative colitis (UC). However, the mucosal concentration of 5-ASA was significantly lower in patients with severe histological inflammation, which further led to a poor response to 5-ASA treatment. Our study aimed to clarify the mechanism of 5-ASA uptake into colonic epithelial cells and to further explore the reason for the decreased colonic mucosal 5-ASA concentration in UC patients. Our results demonstrated that the colonic 5-ASA concentration was notably reduced in DSS-induced colitis mice and inversely correlated with colonic inflammation. 5-ASA was not a substrate of carnitine/organic cation transporter 1/2 (OCTN1/2) or multidrug resistance protein 1 (MDR1), whereas organic anion transporting polypeptide 2B1 (OATP2B1) and sodium-coupled monocarboxylate transporter 1 (SMCT1) mediated the uptake of 5-ASA, with a greater contribution from OATP2B1 than SMCT1. Inhibitors and siRNAs targeting OATP2B1 significantly reduced 5-ASA absorption in colonic cell lines. Moreover, OATP2B1 expression was dramatically downregulated in colon tissues from UC patients and dextran sodium sulfate (DSS)-induced colitis mice, and was also negatively correlated with colonic inflammation. Mechanistically, mixed proinflammatory cytokines downregulated the expression of OATP2B1 in a time- and concentration-dependent manner through the hepatocyte nuclear factor 4 α (HNF4α) pathway. In conclusion, OATP2B1 was the pivotal transporter involved in colonic 5-ASA uptake, which indicated that inducing OATP2B1 expression may be a strategy to promote 5-ASA uptake and further improve the concentration and anti-inflammatory efficacy of 5-ASA in UC.
Subject(s)
Colitis, Ulcerative , Cytokines , Down-Regulation , Mesalamine , Organic Anion Transporters , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/pathology , Animals , Humans , Down-Regulation/drug effects , Organic Anion Transporters/metabolism , Mice , Mesalamine/pharmacology , Mesalamine/therapeutic use , Cytokines/metabolism , Male , Dextran Sulfate , Mice, Inbred C57BL , Colon/metabolism , Colon/pathology , Colon/drug effects , Female , Anti-Inflammatory Agents, Non-Steroidal/pharmacologyABSTRACT
The development of minimally invasive surgery has greatly advanced precision tumor surgery, but sometime suffers from restricted visualization of the surgical field, especially during the removal of abdominal tumors. A 3-D inspection of tumors could be achieved by intravenously injecting tumor-selective fluorescent probes, whereas most of which are unable to instantly distinguish tumors via in situ spraying, which is urgently needed in the process of surgery in a convenient manner. In this study, this work has designed an injectable and sprayable fluorescent nanoprobe, termed Poly-g-BAT, to realize rapid tumor imaging in freshly dissected human colorectal tumors and animal models. Mechanistically, the incorporation of γ-glutamyl group facilitates the rapid internalization of Poly-g-BAT, and these internalized nanoprobes can be subsequently activated by intracellular NAD(P)H: quinone oxidoreductase-1 to release near-infrared fluorophores. As a result, Poly-g-BAT can achieve a superior tumor-to-normal ratio (TNR) up to 12.3 and enable a fast visualization (3 min after in situ spraying) of tumor boundaries in the xenograft tumor models, Apcmin/+ mice models and fresh human tumor tissues. In addition, Poly-g-BAT is capable of identifying minimal premalignant lesions via intravenous injection.
ABSTRACT
BRD9 is a pivotal epigenetic factor involved in cancers and inflammatory diseases. Still, the limited selectivity and poor phenotypic activity of targeted agents make it an atypically undruggable target. PROTAC offers an alternative strategy for overcoming the issue. In this study, we explored diverse E3 ligase ligands for the contribution of BRD9 PROTAC degradation. Through molecular docking, binding affinity analysis, and structure-activity relationship study, we identified a highly potent PROTAC E5, with excellent BRD9 degradation (DC50 = 16 pM) and antiproliferation in MV4-11 cells (IC50 = 0.27 nM) and OCI-LY10 cells (IC50 = 1.04 nM). E5 can selectively degrade BRD9 and induce cell cycle arrest and apoptosis. Moreover, the therapeutic efficacy of E5 was confirmed in xenograft tumor models, accompanied by further RNA-seq analysis. Therefore, these results may pave the way and provide the reference for the discovery and investigation of highly effective PROTAC degraders.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Molecular Docking Simulation , Ubiquitin-Protein Ligases , Humans , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Structure-Activity Relationship , Cell Proliferation/drug effects , Ubiquitin-Protein Ligases/metabolism , Cell Line, Tumor , Mice , Drug Discovery , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/pathology , Hematologic Neoplasms/metabolism , Transcription Factors/metabolism , Transcription Factors/antagonists & inhibitors , Apoptosis/drug effects , Proteolysis/drug effects , Mice, Nude , Mice, Inbred BALB C , Xenograft Model Antitumor Assays , Drug Screening Assays, Antitumor , Bromodomain Containing ProteinsABSTRACT
High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10.
Subject(s)
Adaptor Proteins, Signal Transducing , Antineoplastic Agents , Carcinoma, Hepatocellular , Cell Proliferation , Drug Discovery , Liver Neoplasms , Transcription Factors , Ubiquitin Thiolesterase , YAP-Signaling Proteins , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Ubiquitin Thiolesterase/antagonists & inhibitors , Ubiquitin Thiolesterase/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Structure-Activity Relationship , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , YAP-Signaling Proteins/metabolism , Molecular Structure , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Apoptosis/drug effects , Small Molecule Libraries/pharmacology , Small Molecule Libraries/chemistry , Small Molecule Libraries/chemical synthesis , Cell Line, TumorABSTRACT
BACKGROUND: According to the literatures, triacanthine is isolated from the leaves of Gleditsia triacanthos L. and acts as an anti-hypertensive agent, also cardiotonic, antispasmodic and a respiratory analeptic. The 5-fluorouracil (5-FU) is widely used to treat the patients of colorectal cancer (CRC), but the resistance to 5-FU treatment restricts the therapeutic efficacy of CRC patients. PURPOSE: This study aims to explore a novel therapeutics regimen overcoming CRC resistance to 5-FU. METHODS: The cell proliferation of CRC cells was determined by SRB and colony formation assay. Transwell and wound-healing assay were applied to explore the potential metastatic abilities of CRC cells. qRT-PCR and Western blot were performed to evaluate the level of indicated mRNAs and proteins respectively. Xenograft assay was used to explore the anti-CRC effect of triacanthine. RESULTS: Triacanthine statistically restrained CRC proliferation both in vitro and in vivo. Triacanthine induced cell cycle G1/G0 phase arrest in CRC cells. Meanwhile, triacanthine also inhibited the migrative and invasive abilities of CRC cells. A Venn diagram was generated showing that O-6-Methylguanine-DNA Methyltransferase (MGMT) might be a molecular target of triacanthine in treating CRC. Furthermore, triacanthine plus 5-FU significantly suppressed the cell proliferation of CRC cells compared with single agent treatment alone, and highly synergistic anti-cancer effects were scored when 5-FU was combined with triacanthine in CRC cells. In addition, triacanthine sensitized the anti-cancer activity of 5-FU via regulating Ribonucleotide Reductase Regulatory Subunit M2 (RRM2). MGMT or RRM2 might be novel biomarkers for evaluating the therapeutical efficiency of 5-FU in CRC patients. CONCLUSION: We firstly demonstrated triacanthine suppressed cell proliferation and metastasis abilities and found the novel molecular targets of triacanthine in CRC cells. This is the first study to evaluate the anti-cancer efficiency of triacanthine plus 5-FU. Our study has revealed triacanthine as a pertinent sensitizer to 5-FU, and provided novel strategies for predicting outcomes and reversing resistance of 5-FU therapy.
Subject(s)
Alkaloids , Colorectal Neoplasms , Purines , Humans , Fluorouracil/pharmacology , Oxidoreductases , Colorectal Neoplasms/pathology , Alkaloids/pharmacology , Cell Proliferation , Cell Line, Tumor , Drug Resistance, Neoplasm , ApoptosisABSTRACT
The limited therapeutic outcomes and severe systemic toxicity of chemotherapy remain major challenges to the current clinical antitumor therapeutic regimen. Tumor-targeted drug delivery that diminishes the undifferentiated systemic distribution is a practical solution to ameliorating systemic toxicity. However, the tumor adaptive immune microenvironment still poses a great threat that compromises the therapeutic efficacy of chemotherapy by promoting the tolerance of the tumor cells. Herein, a pluripotential neutrophil-mimic nanovehicle (Neutrosome(L)) composed of an activated neutrophil membrane-incorporated liposome is proposed to modulate the immune microenvironment and synergize antitumor chemotherapy. The prominent tumor targeting capability inherited from activated neutrophils and the improved tumor penetration ability of Neutrosome(L) enable considerable drug accumulation in tumor tissues (more than sixfold that of free drug). Importantly, Neutrosome(L) can modulate the immune microenvironment by restricting neutrophil infiltration in tumor tissue, which may be attributed to the neutralization of inflammatory cytokines, thus potentiating antitumor chemotherapy. As a consequence, the treatment of cisplatin-loaded Neutrosome(L) performs prominent tumor suppression effects, reduces systemic drug toxicity, and prolongs the survival period of tumor-bearing mice. The pluripotential neutrophil-mimic nanovehicle proposed in this study can not only enhance the tumor accumulation of chemotherapeutics but also modulate the immune microenvironment, providing a compendious strategy for augmented antitumor chemotherapy.
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Idiopathic pulmonary fibrosis (IPF) is a fatal and irreversible disease with few effective treatments. Alveolar macrophages (AMs) are involved in the development of IPF from the initial stages due to direct exposure to air and respond to external oxidative damage (a major inducement of pulmonary fibrosis). Oxidative stress in AMs plays an indispensable role in promoting fibrosis development. The oligopeptide histidine transporter SLC15A3, mainly expressed on the lysosomal membrane of macrophages and highly expressed in the lung, has proved to be involved in innate immune and antiviral signaling pathways. In this study, we demonstrated that during bleomycin (BLM)- or radiation-induced pulmonary fibrosis, the recruitment of macrophages induced an increase of SLC15A3 in the lung, and the deficiency of SLC15A3 protected mice from pulmonary fibrosis and maintained the homeostasis of the pulmonary microenvironment. Mechanistically, deficiency of SLC15A3 resisted oxidative stress in macrophages, and SLC15A3 interacted with the scaffold protein p62 to regulate its expression and phosphorylation activation, thereby regulating p62-nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant stress pathway protein, which is related to the production of reactive oxygen species (ROS). Overall, our data provided a novel mechanism for targeting SLC15A3 to regulate oxidative stress in macrophages, supporting the therapeutic potential of inhibiting or silencing SLC15A3 for the precautions and treatment of pulmonary fibrosis.
Subject(s)
Bleomycin , Mice, Inbred C57BL , Oxidative Stress , Pulmonary Fibrosis , Animals , Humans , Male , Mice , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/chemically induced , Macrophages/metabolism , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/pathology , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/deficiency , Oxidative Stress/drug effects , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/chemically induced , Reactive Oxygen Species/metabolism , Signal TransductionABSTRACT
The function of SLC7A11 in the process of ferroptosis is well-established, as it regulates the synthesis of glutathione (GSH), thereby influencing tumor development along with drug resistance in non-small cell lung cancer (NSCLC). However, the determinants governing SLC7A11's membrane trafficking and localization remain unknown. Our study identified SPTBN2 as a ferroptosis suppressor, enhancing NSCLC cells resistance to ferroptosis inducers. Mechanistically, SPTBN2, through its CH domain, interacted with SLC7A11 and connected it with the motor protein Arp1, thus facilitating the membrane localization of SLC7A11 - a prerequisite for its role as System Xc-, which mediates cystine uptake and GSH synthesis. Consequently, SPTBN2 suppressed ferroptosis through preserving the functional activity of System Xc- on the membrane. Moreover, Inhibiting SPTBN2 increased the sensitivity of NSCLC cells to cisplatin through ferroptosis induction, both in vitro and in vivo. Using Abrine as a potential SPTBN2 inhibitor, its efficacy in promoting ferroptosis and sensitizing NSCLC cells to cisplatin was validated. Collectively, SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC.
Subject(s)
Amino Acid Transport System y+ , Carcinoma, Non-Small-Cell Lung , Ferroptosis , Lung Neoplasms , Spectrin , Humans , Amino Acid Transport System y+/metabolism , Biological Transport , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/pharmacology , Glutathione , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Spectrin/metabolismABSTRACT
PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Mice , Animals , Triple Negative Breast Neoplasms/pathology , Proteomics , Cell Proliferation , Cell Cycle Checkpoints , Nitrogen , Cell Line, Tumor , cdc25 Phosphatases , Poly (ADP-Ribose) Polymerase-1 , CDC2 Protein KinaseABSTRACT
G2/M cell cycle checkpoint protein WEE1 kinase is a promising target for inhibiting tumor growth. Although various WEE1 inhibitors have entered clinical investigations, their therapeutic efficacy and safety profile remain unsatisfactory. In this study, we employed a comprehensive virtual screening workflow, which included Schrödinger-Glide molecular docking at different precision levels, as well as the utilization of tools such as MM/GBSA and Deepdock to predict the binding affinity between targets and ligands, in order to identify potential WEE1 inhibitors. Out of ten molecules screened, 50% of these molecules exhibited strong inhibitory activity against WEE1. Among them, compounds 4 and 5 showed excellent inhibitory activity with IC50 values of 1.069 and 3.77 nM respectively, which was comparable to AZD1775. Further investigations revealed that compound 4 displayed significant anti-proliferative effects in A549, PC9, and HuH-7 cells and could also induce apoptosis and G1 phase arrest in PC9 cells. Additionally, molecular dynamics simulations unveiled the binding details of compound 4 with WEE1, notably the crucial hydrogen bond interactions formed with Cys379. In summary, this comprehensive virtual screening workflow, combined with in vitro testing and computational modeling, holds significant importance in the development of promising WEE1 inhibitors.
ABSTRACT
Background and objective: As a partial positive allosteric modulator of the gamma-aminobutyric acid A (GABAA) receptor, dimdazenil was used for the treatment of insomnia with the potential to alleviate associated side effects compared to full agonists. The objective of this trial is to assess the safety, tolerability, food effect and pharmacokinetics following single and multiple doses of dimdazenil in Chinese healthy subjects. Methods: In this phase 1 trial, 36 healthy subjects aged ≥18 years were assigned to receive a single dose of 1.5, 2.5, or 5 mg dimdazenil, with each dose cohort consisting of 12 subjects, and 14 subjects were assigned to receive a multiple 2.5 mg daily dose of dimdazenil for 5 days. Safety, tolerability, and pharmacokinetic characteristics were evaluated. Results: Of the 50 subjects enrolled and 49 completed the trial, the incidences of treatment-emergent adverse events (AEs) in the single-dose groups of 1.5, 2.5, and 5 mg were 16.7%, 58.3% and 66.7% respectively, while 61.5% in the multiple-dose group. There were no serious AEs, deaths, AEs leading to discontinuation or AEs of requiring clinical intervention in any treatment groups. The most treatment-emergent AEs were dizziness (n = 4, 8.2%), hyperuricemia (n = 2, 6.1%), upper respiratory tract infection (n = 2, 6.1%), diastolic blood pressure decreased (n = 2, 6.1%), blood TG increased (n = 2, 6.1%) and RBC urine positive (n = 2, 6.1%). All AEs were mild-to-moderate and transient, and no severe AEs were documented in any study phase. The PK profile of dimdazenil and its active metabolite Ro46-1927 was linear across 1.5-5 mg oral doses in humans. The median Tmax for dimdazenil was in the range of 0.5-1.5 h, and the apparent terminal t1/2z ranged from 3.50 to 4.32 h. Taking Dimdazenil with food may delay Tmax and decrease Cmax, without affecting the total exposure (AUC). No relevant accumulations of dimdazenil and Ro 46-1927 were observed in multiple-dose group. Conclusion: Dimdazenil was generally well tolerated in healthy Chinese subjects after single and 5 days-multiple dosing. The pharmacokinetic properties of dimdazenil are compatible with a drug for the treatment of insomnia. Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR20201978.
ABSTRACT
The tumor microenvironment (TME) is a crucial driving factor for tumor progression and it can hinder the body's immune response by altering the metabolic activity of immune cells. Both tumor and immune cells maintain their proliferative characteristics and physiological functions through transporter-mediated regulation of nutrient acquisition and metabolite efflux. Transporters also play an important role in modulating immune responses in the TME. In this review, we outline the metabolic characteristics of the TME and systematically elaborate on the effects of abundant metabolites on immune cell function and transporter expression. We also discuss the mechanism of tumor immune escape due to transporter dysfunction. Finally, we introduce some transporter-targeted antitumor therapeutic strategies, with the aim of providing new insights into the development of antitumor drugs and rational drug usage for clinical cancer therapy.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Tumor Escape , Tumor Microenvironment , Neoplasms/therapy , Antineoplastic Agents/therapeutic use , ImmunityABSTRACT
BACKGROUND: Nirmatrelvir-ritonavir (NMVr) is a recently developed antiviral agent for treating coronavirus disease 2019 (COVID-19); however, data describing its appropriate use are scarce. This study examined the prevalence of inappropriate use of NMVr in a Chinese hospital setting. METHODS: A multi-centre retrospective chart review was performed for all hospitalized patients who received NMVr between 15 December 2022 and 15 February 2023 in four university-affiliated hospitals in Hangzhou, China. A multi-disciplinary team of experts developed the evaluation criteria. A group of senior clinical pharmacists examined and verified the suitability of NMVr prescriptions. RESULTS: In total, 247 patients received NMVr during the study period, of which 13.4% (n=31) met all the criteria for appropriate use of NMVr. The main types of inappropriate use of NMVr were delayed initiation of treatment (n=147, 59.5%), no dose adjustment for moderate renal impairment (n=46, 18.6%), use in patients with severe-to-critical COVID-19 (n=49, 19.8%), presence of contra-indicated drugâdrug interactions with other medications (n=36, 14.6%), and prescription for patients without a confirmed diagnosis of COVID-19 (n=36, 14.6%). CONCLUSIONS: The proportion of inappropriate use of NMVr was particularly high in the Chinese hospital setting, highlighting the urgent need to improve the appropriate use of NMVr.
Subject(s)
COVID-19 , Ritonavir , Humans , Retrospective Studies , Prevalence , Ritonavir/therapeutic use , COVID-19/epidemiology , COVID-19 Drug Treatment , China/epidemiology , Antiviral Agents/therapeutic use , Hospitals, UniversityABSTRACT
Gastric cancer is the third leading cause of cancer related death worldwide. Due to the complexity and heterogeneity of gastric cancer, the development of targeted drugs is somehow limited, but is urgently needed. Since the expression of Bruton tyrosine kinase (BTK) was significantly associated with the prognosis of gastric cancer patients, we aimed to determine the anti-cancer activity of HZ-A-018, which was a novel derivative of ACP-196, in gastric cancer cells. As a result, HZ-A-018 presented a stronger anti-proliferation activity than ACP-196 via the substantial suppression of AKT/S6 pathway. In addition, HZ-A-018, but not ACP-196, exerted the synergistic effects in combined treatment with 5-FU both in vitro and in vivo, without exacerbating the adverse effects of 5-FU. Mechanismly, the combination of HZ-A-018 and 5-FU remarkably reduced the expression of RRM2, which played an essential role in proliferation and drug sensitivity in gastric cancer cells. In summary, our work demonstrated the stronger anti-cancer activity of HZ-A-018 than ACP-196 in gastric cancer cells, and revealed synergistic effects of HZ-A-018 and 5-FU combination probably through the inhibition of RRM2 via AKT/S6 pathway, thereby providing a promising therapeutic strategy in gastric cancer.
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Vancomycin (VAN) has a narrow therapeutic window and variable pharmacokinetic properties, which require timely monitoring of plasma concentration to adjust the dosage for better effectiveness. A sensitive and quantitative immunochromatographic method was developed to detect VAN in plasma. The linear response range of the method to detect plasma VAN was 1.25-50 µg/mL. The intra- and inter-assay coefficients were 4.68% and 8.81%, respectively, while the recovery was 89.10%-98.32%. The clinical comparative experiment results demonstrated a good correlation (r > 0.90) between the fluorescent immunochromatographic strip test and the mass spectrum. In this study, a simple, rapid, and high-sensitivity immunochromatographic method was established for detecting VAN, which helped establish the basis for further application of monitoring plasma concentration.
Subject(s)
Vancomycin , Chromatography, Affinity/methodsABSTRACT
Mitofusin-2 (MFN2) is a transmembrane GTPase that regulates mitochondrial fusion and thereby modulates mitochondrial function. However, the role of MFN2 in lung adenocarcinoma remains controversial. Here, we investigated the effect of MFN2 regulation on mitochondria in lung adenocarcinoma. We found that MFN2 deficiency resulted in decreased UCP4 expression and mitochondrial dysfunction in A549 and H1975 cells. UCP4 overexpression restored ATP and intracellular calcium concentration, but not mtDNA copy number, mitochondrial membrane potential or reactive oxygen species level. Furthermore, mass spectrometry analysis identified 460 overlapping proteins after independent overexpression of MFN2 and UCP4; these proteins were significantly enriched in the cytoskeleton, energy production, and calponin homology (CH) domains. Moreover, the calcium signaling pathway was confirmed to be enriched in KEGG pathway analysis. We also found by protein-protein interaction network analysis that PINK1 may be a key regulator of MFN2- and UCP4-mediated calcium homeostasis. Furthermore, PINK1 increased MFN2/UCP4-mediated intracellular Ca2+ concentration in A549 and H1975 cells. Finally, we demonstrated that low expression levels of MFN2 and UCP4 in lung adenocarcinoma are associated with poor clinical prognosis. In conclusion, our data suggest not only a potential role of MFN2 and UCP4 in co-regulating calcium homeostasis in lung adenocarcinoma but also their potential use as therapeutic targets in lung cancer.
Subject(s)
Adenocarcinoma of Lung , Calcium , Humans , Calcium/metabolism , Down-Regulation/genetics , Adenocarcinoma of Lung/genetics , Homeostasis/genetics , Protein Kinases/genetics , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolismABSTRACT
Biofilm formation plays an important role in the resistance development in bacteria to conventional antibiotics. Different properties of the bacterial strains within biofilms compared with their planktonic states and the protective effect of extracellular polymeric substances contribute to the insusceptibility of bacterial cells to conventional antimicrobials. Although great effort has been devoted to developing novel antibiotics or synthetic antibacterial compounds, their efficiency is overshadowed by the growth of drug resistance. Developments in nanotechnology have brought various feasible strategies to combat biofilms by interfering with the biofilm life cycle. In this review, recent nanotechnology-based strategies for interfering with the biofilm life cycle according to the requirements of different stages are summarized. Additionally, the importance of strategies that modulate the bacterial biofilm microenvironment is also illustrated with specific examples. Lastly, we discussed the remaining challenges and future perspectives on nanotechnology-based strategies for the treatment of bacterial infection.