Chloroquine Research Articles

Mesoporous Titanium Dioxide Nanoparticles-Poly(N-isopropylacrylamide) Hydrogel Prepared by Electron Beam Irradiation Inhibits the Proliferation and Migration of Oral Squamous Cell Carcinoma Cells.

An urgently needed approach for the treatment of oral squamous cell carcinoma (OSCC) is the development of novel drug delivery systems that offer targeted specificity and minimal toxic side effects. In this study, we developed an injectable and temperature-sensitive composite hydrogel by combining mesoporous titanium dioxide nanoparticles (MTNs) with Poly(N-isopropylacrylamide) (PNIPAAM) hydrogel to serve as carriers for the model drug Astragalus polysaccharide (APS) using electron beam irradiation. The characteristics of MTNs, including specific surface area and pore size distribution, were analyzed, and the characteristics of MTNs-APS@Hyaluronic acid (HA), such as microscopic morphology, molecular structure, crystal structure, and loading efficiency, were examined. Additionally, the swelling ratio, gel fraction, and microscopic morphology of the composite hydrogel were observed. The in vitro cumulative release curve was plotted to investigate the sustained release of APS in the composite hydrogels. The effects on the proliferation, migration, and mitochondrial membrane potential of CAL-27 cells were evaluated using MTT assay, scratch test, and JC-1 staining. The results indicated successful preparation of MTNs with a specific surface area of 147.059 m2/g and an average pore diameter of 3.256 nm. The composite hydrogel displayed temperature-sensitive and porous characteristics, allowing for slow release of APS. Furthermore, it effectively suppressed CAL-27 cells proliferation, migration, and induced changes in mitochondrial membrane potential. The addition of autophagy inhibitors chloroquine (CQ) and 3-methyladenine (3-MA) attenuated the migration inhibition (p < 0.05).

Rebound of multiple infections and prevalence of anti-malarial resistance associated markers following malaria upsurges in Dielmo village, Senegal, West Africa

BackgroundThanks to the scale up of malaria control interventions, the malaria burden in Senegal has decreased substantially to the point that the National Malaria Control Programme plans to achieve malaria elimination by 2030. To guide such efforts, measuring and monitoring parasite population evolution and anti-malarial drugs resistance is extremely important. Information on the prevalence of parasite mutations related to drug resistance can provide a first signal of emergence, introduction and selection that can help with refining drug interventions. The aim of this study was to analyse the prevalence of anti-malarial drug resistance-associated markers before and after the implementation of artemisinin-based combination therapy (ACT) from 2005 to 2014 in Dielmo, a model site for malaria intervention studies in Senegal.MethodsSamples from both malaria patients and Plasmodium falciparum asymptomatic carriers were analysed with high resolution melting (HRM) technique to genotype P. falciparum chloroquine resistance transporter (Pfcrt) gene haplotypes and multidrug-resistant protein 1 (Pfmdr1) gene at codons N86 and Y184.ResultsAmong the 539 samples analysed, 474, 486, and 511 were successfully genotyped for Pfmdr1 N86, Y184, and Pfcrt, respectively. The prevalence of drug resistance markers was high, particularly during the malaria upsurges. Following the scale-up in bed net distribution, only the mutant (86F-like) variant of Pfmdr1 86 was present while during the malaria upsurges the predominance of two types 86Y-86N (43%) and 86F-like (56%) were observed. Most infections (87%) carried the wild type Y-allele at Pfmdr1 184 during the period of nets scale-up while during the malaria upsurges only 16% of infections had wild type and 79% of infections had mixed (mutant/wild) type. The frequency of the mixed genotypes SVMNT-like_CVMNK and SVMNT-like_CVIET within Pfcrt gene was particularly low during bednet scale up. Their frequency increased significantly (P < 0.001) during the malaria upsurges.ConclusionThis data demonstrated the effect of multiple interventions on the dynamics of drug resistance-associated mutations in the main malaria parasite P. falciparum in an endemic village in Senegal. Monitoring drug resistance markers should be conducted periodically to detect threats of emergence or resurgence that could compromise the efficacy of anti-malarial drugs.

Increased DNMT1 Involvement in the Activation of LO2 Cell Death Induced by Silver Nanoparticles via Promoting TFEB-Dependent Autophagy.

The accumulation of exogenous silver nanoparticles (AgNPs) will terminally bring about liver injury, including cell death, where DNA methylation tends to be a crucial epigenetic modulator. The change in the cell autophagy level verified to be closely associated with hepatocyte death has been followed with wide interest. But the molecular toxicological mechanisms of AgNPs in relation to DNA methylation, autophagy, and cell death remain inconclusive. To address the issue above, in LO2 cells treated with increasing concentrations of AgNPs (0, 5, 10, and 20 μg/mL), a cell cytotoxicity assay was performed to analyze the level of cell death, which also helped to choose an optimal concentration for next experiments. An immunofluorescence assay was used to determine the autophagic flux as well as TFEB translocation, with qRT-PCR and western blot being used to analyze the expression level of autophagy-related genes and proteins. According to our findings, in the determination of cell viability, 20 μg/mL (AgNPs) was adopted as the best working concentration. LO2 cell death, autophagy, and TFEB nuclear translocation were induced by AgNPs, which could be inhibited by lysosome inhibitor chloroquine (CQ) or siRNA specific for TFEB. Moreover, AgNP exposure led to DNA hypermethylation, with DNMT1 taking part mainly, which could be obviously prevented by 5-Aza-2'-deoxycytidine (5-AzaC) or trichostatin A (TSA) treatment or DNMT1 knockout in LO2 cells. Our studies suggest that through TFEB-dependent cell autophagy, increased DNMT1 may facilitate cell death induced by AgNPs.

Evaluation of the Efficacy of Artemether/Lumefantrine/Doxycycline Combination against Plasmodium berghei in Mice

Background: Malaria is common in regions like sub-Saharan Africa and South East Asia, where it results in millions of mortalities per year. Resistance to currently available antimalarials further compounds the problem. Drug combination has been demonstrated to be effective in overcoming resistance to antimalarials. This study aimed to assess the efficacy of the combination of Artemether/Lumefantrine (AL) and Doxycycline (DX) against Plasmodium berghei infection in mice. Methods: Thirty Adult Swiss albino mice were inoculated with the chloroquine (CQ)-sensitive P. berghei NK65 strain. The curative test involved oral administration of any of DX, AL, AL/DX, or Chloroquine (CQ) to mice with established infections, while the suppressive test was performed by treating mice shortly after parasite inoculation. Parasitemia levels were monitored using thin smears stained with Giemsa solution. Mean Survival Time (MST) was determined for each group. Results: In the curative test, DX, AL, and AL/DX exhibited parasitemia inhibitions of 81.4%, 94.5%, and 93.2%, respectively, while CQ achieved 93.5% inhibition. MST was significantly extended by DX, AL, and AL/DX treatments compared to negative control (NC). In the suppressive test, parasitemia inhibitions were 79.9%, 96.1%, 95.5%, and 94.9% for DX, AL, AL/DX, and CQ, respectively. The administration of DX, AL, and AL/DX also significantly prolonged MST compared to NC. Conclusion: The study demonstrates that the drug combination, particularly AL/DX, exhibits significant antimalarial effects in both curative and suppressive tests. The combination treatments led to substantial reductions in parasitemia levels and extended mean survival time, indicating their potential as effective antimalarial strategies. These findings highlight the promising role of drug combinations in addressing malaria infections and suggest avenues for further investigation and development of combination therapies.

AN UNUSUAL MALARIA CASE: MIXED INFECTION? RESISTANCE? MALADAPTIVE PATIENT?

Malaria, a disease known since ancient times and constantly struggled by human beings, still maintains its currency as an important cause of morbidity and mortality today. Although no domestic cases have been observed in Turkey since 2010, around 200-250 malaria cases originating from abroad are observed every year. Resistance to many parasitic drugs has developed over the years since chloroquine resistance emerged in the 1970s. Artemisinin resistance was reported by WHO in Cambodia, Laos, Myanmar, Thailand and Vietnam in 2013 due to P. falciparum malaria, and resistance has been reported also in South Africa and Rwanda recently. It has been shown that resistance development is due to the Kelch 13 mutation detected in parasite and this leads to delayed clearance. According to WHO data, artemether-based combined therapy is still effective in the treatment of patients infected with artemisinin-resistant P. falciparum strains, but possible treatment unresponsiveness is followed meticulously by WHO. Our case is remarkable for its third recurrence despite artemether-based combined therapy twice in 28 days, and its persistent treatment response after quinine and doxycycline treatment.

Composite hydrogel based on chemically modified gelatin and PVA containing graphene oxide nanoparticles (CHGP-GOn)

The increased consumption of medications such as Chloroquine (CQN) during the Covid-19 pandemic, the excretion of this drug leading to an overload of CQN and its metabolites in sewage treatment plants, increased the necessity to adequate treatment for their removal. Water treatment using advanced processes can be enhanced through the utilization of adsorbent and absorbent materials, facilitating the removal of hard-to-treat compounds and enabling material reusability. The use of nanoparticles offers desirable attributes responsible for the adsorption process, maximising the feature of water treatment materials. In this context, graphene oxide exhibits high surface area and significant adsorption capacity due to its abundance of desirable functional groups for adsorbing contaminant molecules. However, the lixiviation from these materials represents an environmental problem. The functionalization of adsorbent materials with nanoparticles has been used to minimise the loss of nano-compounds. In this way, composite hydrogels synthesized with graphene oxide have demonstrated adsorption and absorption properties for emerging contaminants, including pharmaceuticals. Therefore, a composite hydrogel based on chemically modified gelatin and PVA containing graphene nanoparticles, with resistant reticulation and non-toxic compounds, synthesized for the first time, was employed for the removal of CQN from aqueous media. This hydrogel superabsorbent with morphological rough shows 175% capacity of swelling, positive tendency of charge on natural pH due to diverse functional groups, as well as point of zero charges at pH 9.1, amorphous features. The batch removal tests demonstrated a superabsorbent material (175% swelling), showing the best removal in Qe of 13.20 mg g −1 of Chloroquine, as well as a superior performance at natural pH. The adsorption kinetics were best described by the Elovich model, indicating multi-step resistance with intraparticle diffusion as the rate-limiting step, equilibrium in 240 min and a maximum adsorption capacity of 13.31 mg g−1. Furthermore, the isotherm exhibited spontaneous and exothermic adsorption, with low reversibility and randomness in the adsorption system. Besides, the maximum experimental adsorption capacity was 52.98 mg L-1 in 288 K. The material demonstrated promising reusability, retaining its adsorption capacity over three adsorption cycles and values of 14.26 followed by 4.830 and 2.280 mg g- 1, respectively. In conclusion, the composite hydrogel based on graphene oxide shows great potential as an efficient and eco-friendly approach for removing emerging contaminants, particularly pharmaceuticals like CQN, from aqueous environments.

Synthesis and antimalarial activity of novel 3-substituted chloroquine derivatives

The synthesis and characterization of a series of new 3-substituted chloroquine (CQ) derivatives are reported along with their antimalarial activity against CQ-sensitive, 3D7, and CQ-resistant, Dd2, strains of Plasmodium falciparum. The new CQ derivatives stem from the aroylation of 3-aminochloroquine, which in turn is prepared in four efficient steps from 4,7-dichloroquinoline. Variation of the aroylation substituents and ring substitution patterns reveal that 4-substitution with electron-withdrawing moieties results in the lowest IC50 values, both in the same order of magnitude as CQ itself for the 3D7 strain. Given its activity against the resistant Dd2 strain, the 4-chlorobenzamido-CQ derivative is chosen as the lead compound for potential use in combination therapy.

JSI-124 inhibits cell proliferation and tumor growth by inducing autophagy and apoptosis in murine malignant mesothelioma.

Malignant pleural mesothelioma (MPM), mainly caused by asbestos exposure, has a poor prognosis and lacks effective treatment compared with other cancer types. The intracellular transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed and hyperactivated in most human cancers. In this study, the role of STAT3 in murine MPM was examined. Inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway with the selective inhibitor JSI-124 has an antitumor effect in murine MPM. Specifically, we demonstrated that JSI-124 inhibits murine MPM cell growth and induces apoptotic and autophagic cell death. Exposure of RN5 and AB12 cells to JSI-124 resulted in apoptosis via the Bcl-2 family of proteins. JSI-124 triggered autophagosome formation, accumulation, and conversion of LC3I to LC3II. Autophagy inhibitors, Chloroquine (CQ) and Bafilomycin A1 (Baf-A1), inhibited autophagy and sensitized RN5 and AB12 cells to JSI-124-induced apoptosis. Our data indicate that JSI-124 is a promising therapeutic agent for MPM treatment.

Pyronaridine: a review of its clinical pharmacology in the treatment of malaria.

Pyronaridine-artesunate was recently strongly recommended in the 2022 update of the WHO Guidelines for the Treatment of Malaria, becoming the newest artemisinin-based combination therapy (ACT) for both uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Pyronaridine-artesunate, available as a tablet and paediatric granule formulations, is being adopted in regions where malaria treatment outcome is challenged by increasing chloroquine resistance. Pyronaridine is an old antimalarial agent that has been used for more than 50 years as a blood schizonticide, which exerts its antimalarial activity by interfering with the synthesis of the haemozoin pigment within the Plasmodium digestive vacuole. Pyronaridine exhibits a high blood-to-plasma distribution ratio due to its tendency to accumulate in blood cells. This feature is believed to play a crucial role in its pharmacokinetic (PK) properties and pharmacological activity. The PK characteristics of pyronaridine include rapid oral absorption, large volumes of distribution and low total body clearance, resulting in a long terminal apparent half-life. Moreover, differences in PK profiles have been observed between healthy volunteers and malaria-infected patients, indicating a potential disease-related impact on PK properties. Despite a long history, there is only limited knowledge of the clinical PK and pharmacodynamics of pyronaridine, particularly in special populations such as children and pregnant women. We here provide a comprehensive overview of the clinical pharmacology of pyronaridine in the treatment of malaria.

Hsa_circ_0000585 promotes chemoresistance to cis-platin in epithelial cells of ovarian cancer by modulating autophagy

BackgroundChemoresistance, i.e., resistance to cisplatin (DDP), has been a major obstacle to ovarian cancer treatment. It has been found that circular RNAs (circRNAs) play vital roles in the tumorigenesis various cancers by regulating autophagy, while few studies focusing on cisplatin-resistance ovarian cancer (CROC). MethodsThe expressions of the circRNAs were detected by qRT-PCR. Short hairpin RNA targeting circRNA was used to explore the biological functions of the circRNA. Cell viability, autophagic flux, immunofluorescence, and xenograft tumors experiments were performed to further illustrate the underlying mechanisms. ResultsHsa_circ_0000585 was increased in cisplatin-resistant SKOV3/DDP cells. Stably knocking down hsa_circRNA_0000585 expression in SKOV3/DDP cells was established by RNA interference. We found that downregulation of hsa_circ_0000585 significantly enhanced the sensitivity of DDP/SkOV3 cells to DDP. In vivo study, hsa_circRNA_0000585 knockdown significantly decreased tumor volume in nude mice. Under the measurements of western blot and cellular immunofluorescence, hsa_circ_0000585 knockdown significantly inhibited the expression of Beclin1 and P62, indicating the autophagic flux was inhibited. Administrations with autophagic inhibitor “Chloroquine (CQ)” and autophagy activator “QX77” further confirmed that hsa_circ_0000585 knockdown resulted in autophagy inhibition. ConclusionsOverall, this study provided a new insight into the role of circRNAs in the mechanism of DDP-resistance in ovarian cancer. Hsa_circRNA_0000585 may be promising therapeutic targets for the enhancement of the sensitivity of ovarian cancer cells to cisplatin-mediated chemotherapy.

Evaluation of Retinal Toxicity by SD-OCT due to Long-Term Exposure to Hydroxycholorquine among Rheumatoid Arthritis Patients

Background Hydroxychloroquine is used increasingly in the management of a variety of autoimmune disorders, with well-established roles in dermatology and rheumatology and emerging roles in oncology. However, Hydroxychloroquine and chloroquine (CQ) have been associated with irreversible visual loss due to retinal toxicity. Cessation of the use of hydroxychloroquine at an early stage of damage might prevent functional loss; however, after maculopathy has developed, cessation of the drug does not show clinical recovery. Because discontinuation of Therapy may reverse retinal toxicity, early detection of toxicity changes is vitally important. Objective to evaluate the involvement of retina in hydroxychloroquine (HCQ) retinopathy among rheumatoid arthritis patients using data from spectral domain optical coherence tomography (SDOCT) and to correlate toxicity with dose, duration of use and cumulative effect of HCQ. Patients and Methods Cross sectional Study. In total 13 patients (26 eyes) attending the rheumatological outpatient clinic of El Demerdash hospital, from October 2019 to February 2020 were enrolled in the study after the approval of the research ethical committee in the Faculty of Medicine, Ain Shams University. A full history was taken from the patients and full ophthalmological examination was done. In our study we perform OCT for all patients by using the Nidek RS-3,000 Advance SD-OCT with the “Macula Map” protocol that imaged a 6 × 6 mm area with 64 raster B-scans, each composed of 1024 A-scans. Results The study showed that was highly significant negative correlation between duration of exposure and CMT (p-value =0.008) and highly significant negative correlation between cumulative dose and CMT (p-value =0.005). Also, there was statistically significant negative correlation between age and thickness of inner and outer nasal quadrant (p-value= 0.015, p-value= 0.001) respectively and between age and inner and outer superior quadrant (p-value= 0.048, p-value= 0.000) respectively, in ETDRS thickness map. It also found statistically significant negative correlation between daily dose and thickness of outer nasal quadrant of thickness map (p-value= 0.045). Conclusion The present study show the presence / absence of retinal toxicity in rheumatoid arthritis patients use hydroxychloroquine for 5years or more using SD-OCT and found a statistically significant negative correlation between central macular thickness and cumulative dose of HCQ and between central macular thickness and duration of HCQ use.

Helicobacter pylori infection induces autophagy via ILK regulation of NOXs-ROS-Nrf2/HO-1-ROS loop.

Reactive oxygen species (ROS) can regulate the occurrence of autophagy, and effective control of the balance between ROS and autophagy may be an important strategy for Helicobacter pylori induced gastric-related diseases. In this study, infection with H. pylori led to a lower level of ILK phosphorylation and increased ROS generation. Knockdown of ILK enhanced total ROS generation, and upregulated NADPH oxidase (NOX) subunit p22-phox levels. Inhibition of NOXs affected total ROS generation. The inhibition of NOX and ROS generation reduced Nrf2 and HO-1 levels, and knockdown of ILK significantly enhanced Nrf2 levels in H. pylori-infected GES-1 cells. Activation of Nrf2 by DMF decreased ROS levels. Therefore, NOX-dependent ROS production regulated by ILK was essential for activation of Nrf2/HO-1 signaling pathways in H. pylori-infected GES-1 cells. Beclin1, ATG5 and LC3B-II levels were higher both in H. pylori-infected and ILK-knockdown GES-1 cells. In NAC-pretreated GES-1 cells infected with H. pylori, the LC3B-II level was decreased compared to that in cells after H. pylori infection alone. Stable low expression of ILK with further knockdown of Beclin1 or ATG5 significantly reduced LC3B-II levels in GES-1 cells, while with the addition of the autophagy inhibitor chloroquine (CQ), LC3B-II and p62 protein levels were both remarkably upregulated. H. pylori accelerated the accumulation of ROS and further led to the induction of ROS-mediated autophagy by inhibiting ILK levels. Together, these results indicate that H. pylori infection manipulates the NOX-ROS-Nrf2/HO-1-ROS loop to control intracellular oxygen stress and further induced ROS-mediated autophagy by inhibiting ILK levels.

Cezanne promoted autophagy through PIK3C3 stabilization and PIK3C2A transcription in lung adenocarcinoma

Osimertinib is a promising approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for treating patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations, however, almost all patients develop resistance to Osimertinib eventually limiting the long-term efficacy. Autophagy is a vital cellular recycling process promoting Osimertinib resistance. Identifying accurate and efficient autophagy-regulatory factors is of great significance in reducing Osimertinib resistance. This study identified Cezanne, a member of the ovarian tumor protease (OTU)-deubiquitinating family, as an autophagy regulator. Cezanne was highly expressed in Osimertinib-resistant cells, and Cezanne overexpression promoted Osimertinib resistance, while chloroquine (CQ), an autophagy inhibitor, reverted this process. In the Cezanne-overexpressing cells, autophagy was activated even in the absence of autophagy inducers rapamycin and Earle’s Balanced Salt Solution (EBSS). Further study showed that Cezanne stabilized PIK3C3 by deubiquitinating K48-linked ubiquitination at Lysine 322. Surprisingly, as a compensatory mechanism of PI3P generation, PIK3C2A was shown to be upregulated by Cezanne by promoting its transcription in a POLR2A-dependent way. Based on these results, Cezanne also accelerates EGFR recycling which may explain the mechanism mediating Cezanne expression and Osimertinib resistance. In conclusion, this study establishes a new model connecting Cezanne, autophagy, and Osimertinib resistance, opening new avenues to explore the effect of Cezanne and autophagy in LUAD.

Differential Regulation of Autophagy on Urine-Concentrating Capability through Modulating the Renal AQP2 Expression and Renin-Angiotensin System in Mice.

Autophagy, a cellular process of "self-eating", plays an essential role in renal pathophysiology. However, the effect of autophagy on urine-concentrating ability in physiological conditions is still unknown. This study aimed to determine the relevance and mechanisms of autophagy for maintaining urine-concentrating capability during antidiuresis. The extent of the autophagic response to water deprivation (WD) was different between the renal cortex and medulla in mice. Autophagy activity levels in the renal cortex were initially suppressed and then stimulated by WD in a time‑dependent manner. During 48h WD, the urine-concentrating capability of mice was impaired by rapamycin but not 3-Methyladenine, accompanied by the suppressed renal aquaporin 2 (AQP2), V2 receptor (V2R), renin, and angiotensin-converting enzyme (ACE) expression, and the levels of prorenin/renin, angiotensin II (AngII), and aldosterone in the plasma and urine. In contrast, 3-Methyladenine and chloroquine suppressed the urine-concentrating capability in WD72 mice, accompanied by downregulation of AQP2 and V2R expression in the renal cortex. 3-Methyladenine and chloroquine further increased AQP2 and V2R expression in the renal medulla of WD72 mice. Compared to 3-MA and CQ, Rapa administration yielded completely opposite results on the above parameters in WD72 mice. In addition, 3-Methyladenine and chloroquine abolished the upregulation of prorenin/renin, AngII, and aldosterone levels in the plasma and urine in WD72mice. Taken together, our study demonstrated that autophagy regulated urine-concentrating capability through differential regulation of the renal AQP2/V2R and ACE/AngII signaling during WD.

CHLOROQUINE INDUCED MACULAR TOXICITY IN A PATIENT LATER DEVELOPING SECTOR RETINITIS PIGMENTOSA: A CASE REPORT.

To describe how underlying retinal diseases, such as retinitis pigmentosa, increase the risk of chloroquine-induced macular toxicity. Observational case report. We present the case of a 57-year-old woman being annually followed-up in the Ophthalmology service due to a systemic treatment with chloroquine (CQ). The explorations were successive normal, until a 10:2 visual field (VF) shows central defects in both eyes. Despite CQ treatment is discontinued, 10:2 VF reveal slowly progressive macular defects. During follow-up, fundus examination disclosed bone spicules in the inferonasal middle periphery: the electroretinogram (ERG) shows slow amplitude responses under scotopic conditions and the electrooculogram (EOG) also shows pathological responses. Therefore, the diagnosis of sector retinitis pigmentosa plus chloroquine maculopathy is made. Currently, the slow but constant progression of both peripheral and central defects is evident, despite having discontinued CQ treatment more than 15 years ago. Underlying retinal diseases seem to increase the risk of photoreceptor damage when undergoing a toxic insult. Thus, we hypothesize a potential interplay between retinal dystrophies and toxic maculopathy induced by CQ, and the influence of each of them in the evolution and prognosis of the other.

Reversing immune evasion using a DNA nano-orchestrator for pancreatic cancer immunotherapy.

Immune evasion caused by the paucity of MHCI is a prominent characteristic of pancreatic adenocarcinoma (PAAD), which is thought to underlie dysfunctional even absent adaptive T cell immunity and is responsible for ineffective immunotherapy. Here, we report a ROS-responsive DNA nano-orchestrator to cascade reverse MHC I-associated immune evasion and boost anti-tumor T cell stimulation, stimulating the activation of tumoricidal immunity against PAAD. Chloroquine phosphate (CQP) as an autophagy inhibitor was first encapsulated with ferritin, and via DNA modular self-assembly technology, the generated ferritin nanocores (FNC) were then caged into ROS-responsive CpG-DNA nanoframe. After systemic injection, the FNC-laden DNA nanoframe (FNC@NF) was passively enriched in tumor tissues in which the DNA nanoframe was cleaved upon the ROS stimulation. Oligodeoxynucleotide (ODN) with CpG motifs was detached and functioned as a TLR9 agonist. The liberated FNC was then endocytosed in an actively targeted manner by binding to transferrin receptor 1. In the lysosome, CQP was burst released from FNC due to acid-triggering. Through CQP-mediated autophagy abrogation, MHC-I molecules were preserved. We demonstrated that cascade inhibiting autophagy and boosting TLR9 stimulation via our proposed DNA-based hybrid nanosystem restored MHC I on the tumor cell surface and reshaped the antigen presentation of DCs, and ultimately reversed immune evasion and synergistically reinforced the activation of cytotoxic T cells against PAAD cells. In sum, our work provides an alternative strategy for cascade reversing immune evasion and boosting anti-tumor T cell stimulation and holds great potential for pancreatic cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A DNA nano-orchestrator was created by sequentially assembling chloroquine phosphate-laden ferritin nanocores with ROS-responsive CpG-DNA nanoframe. Through cascade inhibiting autophagy and boosting TLR9 stimulation, the nano-orchestrator efficiently reversed MHC I-associated immune evasion and augmented anti-tumor T cell stimulation, which ultimately activated tumoricidal immunity against pancreatic adenocarcinoma.

Programmed T cells infiltration into lung metastases with harnessing dendritic cells in cancer immunotherapies by catalytic antigen-capture sponges.

T lymphocytes served as immune surveillance to suppress metastases by physically interacting with cancer cells. Whereas tumor immune privilege and heterogeneity protect immune attack, it limits immune cell infiltration into tumors, especially in invasive metastatic clusters. Here, a catalytic antigen-capture sponge (CAS) containing the catechol-functionalized copper-based metal organic framework (MOF) and chloroquine (CQ) for programming T cells infiltration is reported. The intravenously injected CAS accumulates at the tumor via the folic acid-mediated target and margination effect. In metastases, Fenton-like reaction induced by copper ions of CAS disrupts the intracellular redox potential, i.e., chemodynamic therapy (CDT), thereby reducing glutathione (GSH) levels. Furthermore, CQ helps inhibit autophagy by inducing lysosomal deacidification during CDT. This process leads to the breakdown of self-defense mechanisms, which exacerbates cytotoxicity. The therapies promote the liberation of tumor-associated antigens, such as neoantigens and damage-associated molecular patterns (DAMPs). Subsequently, the catechol groups present on CAS perform as antigen reservoirs and transport the autologous tumor-associated antigens to dendritic cells, resulting in prolonged immune activation. The CAS, which is capable of forming in-situ, serves as an antigen reservoir in CDT-mediated lung metastasis and leads to the accumulation of immune cells in metastatic clusters, thus hindering metastatic tumors.

Protective Autophagy Attenuates the Cytotoxicity of MTI-31 in Renal Cancer Cells by Activating the ERK Pathway.

Themammaliantargetof rapamycin (mTOR)is a key regulatory molecular target to treat cancer, and MTI-31 is a potent mTOR inhibitory agent for the therapeutically target of the renal cell carcinoma (RCC). However, the therapeutic efficacy of MTI-31 is limited by multiple factors, including autophagy. MTI-31 can activate cells to generate autophagy, which may in turn indirectly affect cell proliferation and apoptosis. We aimed to observe changes in cell protective autophagy via the ERK pathway and explore the potential mechanism underlying drug resistance of RCC cells to MTI-31. Different concentrations of 786-O and RCC4 cells were co-cultured with MTI-31 for distinct durations. The result of autophagy marker detection by Western blot showed that MTI-31 could induce RCC cells to produce autophagy in a dose and time-dependent manner. After treating the RCC cells with the autophagy inhibitor chloroquine (CQ), CCK8 and Western blot assays demonstrated that CQ could effectively enhance cell apoptosis induced by MTI-31 and that the autophagy induced by MTI-31 was cytoprotective. In addition, CCK8 and Western blot demonstrated that MTI-31 exerted its effect by activating the ERK pathway rather than the JNK or p38 pathway. The use of the ERK inhibitor AZD6244 to block the ERK pathway could effectively promote cell apoptosis induced by MTI-31. AZD6244 attenuated the autophagy induced by MTI-31 and increased the cytotoxicity of MTI-31. Western blot also demonstrated that MTI-31-induced autophagy was mediated by the downstream regulators of ERK pathways, including Beclin-1 and Bcl-2. It demonstrated that the MTI-31 mediated activation ERK pathway is associated with the induction of autophagy, and autophagy can attenuate the cytotoxicity of MTI-31 on RCC cells. In summary, inhibition of ERK pathway-mediated autophagy can rectify drug resistance to MTI-31 effectively.

Controllable synthesis of nanorod nickel doped cobalt molybdate as an efficient heterogeneous catalyst of peroxymonosulfate for degradation of chloroquine phosphate

This study reports the preparation of an affordable Ni-doped CoMoO4 catalyst (NiXCo1−XMoO4 (X = 0–1)) via a hydrothermal method by substituting Co with Ni and investigated the performance and mechanism of NiXCo1−XMoO4 catalyzing peroxymonosulfate (PMS) to degrade organic pollutants for the first time. Based on characterization, it can be observed that the synthesized Ni0.5Co0.5MoO4 catalyst exhibited excellent surface properties and structural stability. Under optimal conditions, Ni0.5Co0.5MoO4 and PMS synergistically achieved over 95% degradation of chloroquine phosphate (CQP) within 20 min, demonstrating superior performance. The degradation system maintained high efficiency under interference different interfering substances in aqueous media, exhibiting excellent tolerance and practicality. Elemental analysis and mechanistic studies of the catalyst showed that Ni doping promoted the reduction between Co2+/Co3+ and Mo4+/Mo6+, which is critical for catalyst durability and reusability. The quenching experiment and electron paramagnetic resonance (EPR) show that the 1O2 generated through non-free radical pathways represented the predominant reactive species. A total of 19 intermediates were detected by LC-MS during degradation and possible pathways for CQP degradation were proposed and toxicity evaluation. After 5 cycles, the catalyst still showed good stability. Ni0.5Co0.5MoO4 challenges including poor activation, metal ion leaching and low recovery of transition metal catalysts were addressed. This work offers new insights for the design of atom-doped spinel catalysts for catalytic oxidation and mechanism research. The Ni0.5Co0.5MoO4/PMS catalytic system can be extended to the treatment of other organic pollutants and even applied in the processing of high-concentration organic wastewater that requires rapid treatment, offering broader prospects for practical applications.

Dysregulation of Histone Deacetylases Inhibits Trophoblast Growth during Early Placental Development Partially through TFEB-Dependent Autophagy-Lysosomal Pathway.

Dysregulated biological behaviors of trophoblast cells can result in recurrent spontaneous abortion (RSA)-whose underlying etiology still remains insufficient. Autophagy, a conserved intracellular physiological process, is precisely monitored throughout whole pregnancy. Although the exact mechanism or role remains elusive, epigenetic modification has emerged as an important process. Herein, we found that a proportion of RSA patients exhibited higher levels of autophagy in villus tissues compared to controls, accompanied with impaired histone deacetylase (HDAC) expression. The purpose of this study is to explore the connection between HDACs and autophagy in the pathological course of RSA. Mechanistically, using human trophoblast cell models, treatment with HDAC inhibitor (HDACI)-trichostatin A (TSA) can induce autophagy by promoting nuclear translocation and transcriptional activity of the central autophagic regulator transcription factor EB (TFEB). Specifically, overactivated autophagy is involved in the TSA-driven growth inhibition of trophoblast, which can be partially reversed by the autophagy inhibitor chloroquine (CQ) or RNA interference of TFEB. In summary, our results reveal that abnormal acetylation and autophagy levels during early gestation may be associated with RSA and suggest the potential novel molecular target TFEB for RSA treatment.