Chloroquine Research Articles

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.

Exploring the Potential of Crude Methanolic Leaf Extract of Gossypium Hirsutum in Malaria Treatment, Pain Relief, and Inflammation Reduction

The increasing resistance of Plasmodium falciparum to standard anti-malarial drugs has led to a search for new compounds with antimalarial properties. Throughout history, various plants have been used for the treatment of malaria. Gossypium hirsutum, a plant commonly used in Ondo state for malaria treatment, was the focus of this study. The crude extracts of Gossypium hirsutum were evaluated for their anti-plasmodial, analgesic, and anti-inflammatory properties. To assess the anti-plasmodial effect, Plasmodium berghei was inoculated into 12 mice divided into four groups, with three mice in each group. Groups 1 and 2 were treated with doses of 200mg/kg.bw and 400mg/kg.bw of the crude plant extract, respectively. Group 3 received 5mg/kg.bw of chloroquine phosphate, while group 4 received normal saline. The analgesic effects were evaluated using the Eddy's hot plate method and the Tail flick method in mice. The anti- inflammatory effect was assessed using egg albumin-induced paw edema in rats. The crude methanolic extracts of Gossypium hirsutum demonstrated activity against Plasmodium parasites and a significant anti-inflammatory effect, suppressing paw edema by 49.7%. Animals administered with the extracts showed increased resptime to thermal pain induction in both the hot plate and tail flick methods, similar to the effect oonse bserved with the standard drug. The crude plant extract reduced parasitemia in mice by 79.2%, accompanied by a slight but statistically insignificant decrease in packed cell volume (PCV) and the weight of treated animals. Overall, the crude extract of Gossypium hirsutum exhibited effectiveness in managing malaria, along with a moderate analgesic and anti-inflammatory potential. These findings suggest that the plant contains active compounds with promising antimalarial effects, which could be further isolated and studied.

Simultaneous Inhibition of Heat Shock Response and Autophagy with Bimetallic Mesoporous Nanoparticles to Enhance Mild‐Temperature Photothermal Therapy

Mild‐temperature photothermal therapy (MPTT) is a promising tumor therapeutic modality because it can avoid the damage of normal tissues near the tumor caused by excessive heat. However, its therapeutic effect is severely impaired because tumor cells can develop heat resistance and self‐repair by activating heat shock response and cell autophagy. Herein, a tannic acid–iron ion metal organic framework‐coated, chloroquine (CQ)‐loaded mesoporous PdPt nanosystem (TF‐CQ@mPdPt) is developed to enhance MPTT by simultaneous suppression of heat shock response and autophagy. TF‐CQ@mPdPt exhibits good peroxidase (POD)‐mimic activity and photothermal performance. As a result, the reactive oxygen species generated by POD‐mediated decomposition of endogenous hydrogen peroxide damage mitochondria, leading to limitation of adenosine triphosphate supply, which suppresses the upregulation of heat shock proteins of tumor cells during MPTT, making tumor cell more sensitive to heat stress. Concurrently, CQ released from TF‐CQ@mPdPt during MPTT inhibits cell autophagy, thereby interrupting the self‐repair pathway of tumor cells. Consequently, TF‐CQ@mPdPt‐mediated MPTT significantly enhances its therapeutic effect, effectively inhibiting tumor progression in 4T1 tumor‐bearing mice. This study presents a novel strategy to enhance MPTT by simultaneously suppressing heat shock response and autophagy.

Binary regulation of photoelectron-heterojunction Sg-CN/BMO using sulfur-doping and oxygen vacancy construction for boosting chloroquine degradation

Photoelectrocatalysis (PEC) is a promising method for contaminant treatment, the preparation of photoelectrocatalyst is momentous for realization of superior PEC degradation efficiency. Herein, sulfur-doping g-CN and oxygen vacancy regulated bismuth molybdate heterojunction Sg-CN1/BMO5 was synthesized for chloroquine phosphate (CQ) degradation. Benefiting from band gap re-building and enhanced electronic transmission, the heterojunction displayed outstanding photoelectrocatalytic ability, and 90.2% of CQ can be degraded within 120 min. The degradation activity of Sg-CN1/BMO5 has been testified by pseudo-first-order rate constant, which was 3.03 and 2.66 folds of g-CN and BM. The enhanced photoelectrocatalytic effect was attributed to the boosted visible light adsorption ability, recombination suppression of photogenerated carriers and accelerated charge transfer process of the heterojunction. Radical capture experiments and electron spin-resonance (ESR) results revealed that the hydroxyl radical (OH), superoxide radical (O2–) and hole (h+) dominated the CQ degradation. Furthermore, the CQ degradation pathway and toxicity evaluation of intermediates were proposed based on DFT calculation and LC-MS identification.

Efficient degradation of chloroquine phosphate by peroxymonosulfate activated using reusable lanthanide cobalt-copper perovskite-cerium dioxide composite catalyst: Performance, mechanism and degradation pathway

In recent years, chloroquine phosphate (CQP) has been widely used as a specific drug for treating COVID-19. Because of its biological toxicity, the release of CQP into water is bound to have a potential impact on human health. It is urgent to find a reusable and efficient catalyst to treat a large number of CQP wastewater. Currently, perovskite-type catalysts are gradually entering the field of advanced oxidation process, but there are still some problems such as high particle aggregation and limited reaction contact. Here, LaCo0.5Cu0.5O3-CeO2 was prepared by sol-gel method and used to activate peroxymonosulfate (PMS) to degrade CQP for the first time. The LaCo0.5Cu0.5O3-CeO2 material has better stability, larger specific surface area and more uniform pore structure. Under the conditions of 0.2 g/L catalyst and 1.0 mM PMS, 20 mg/L CQP can be completely degraded within 8 min and is suitable for a wide pH range and complex water quality. Superoxide free radical (·O2-) and the singlet oxygen (1O2) are the main free radicals to degrade CQP. The addition of CeO2 makes Ce4+/Ce3+ participate in the redox cycles between Co3+/Co2+ and Cu2+/Cu+, realizing the multipath electron transfer. In addition, LaCo0.5Cu0.5O3-CeO2/PMS system can degrade CQP into low toxicity products through different pathways, ultimately mineralizing it into inorganic small molecules. In general, LaCo0.5Cu0.5O3-CeO2 has more reasonable structure, efficient and durable catalytic performance, anti-interference ability and low ion leaching level, which provides a new idea for preparing heterogeneous catalyst to activate PMS to treat pharmaceutical wastewater, and has broad practical application prospects.

Temozolomide and chloroquine co-loaded mesoporous silica nanoparticles are effective against glioma

The past decades have witnessed great progress in nanoparticle‐based cancer‐targeting drug delivery systems, but their therapeutic potentials is yet to be fully exploited. In this research, temozolomide (TMZ) and chloroquine (CQ) were loaded into the mesoporous silica nanoparticles (MSNs), the surface was coated with polydopamine (PDA), and the complex was coupled with arginine-glycine-aspartic (RGD) to successfully prepare TMZ/CQ@MSN-RGD. RGD-MSNs accumulated more in the cell and tumor models than in unmodified MSNs in the in vitro and in vivo experiments and can directly induce apoptosis and autophagy in tumor cells. In addition, TMZ/CQ@MSN-RGD therapy enhanced the apoptosis effect of the RGD-MSNs in glioma. Therefore, the combination of autophagy inhibitor with chemotherapy drugs in nanocarriers may promote therapeutic efficacy in treating glioma.

A biodegradable hollow nanoagent enables a boosted chemodynamic therapy by simultaneous autophagy inhibition and macrophage reeducation

Various therapeutic strategies, including chemotherapy, radiotherapy, photothermal therapy (PTT), and immunotherapy have been applied in cancer therapy. However, intrinsic or acquired therapeutic resistance is the main obstacle that attenuates the treatment effect of the therapeutic reagents used in these strategies. Studies have shown that autophagy and immunosuppressive tumor-associated macrophages (TAMs), as internal and external resistance mechanisms, would significantly compromise the effectiveness of cancer treatment. Therefore, selectively blocking the autophagy and repolarizing TAMs to anti-tumor phenotype (M1) will be effective for cancer treatments. Herein, an ambidextrous strategy that simultaneously inhibited autophagy and reeducated TAMs to promote anti-tumor therapy meditated by the iron-based nanocarriers was reported. The released Fe (II) ion reacted with the released artemisinin (ART) to produce ROS for chemodynamic therapy (CDT). The chloroquine (CQ) was used to inhibit autophagy in cancer cells and reset TAMs from the M2 phenotype to the M1 phenotype, eliminating the resistance of cancer cells and realizing an augmented therapeutic effect. This work provides a promising way for augmenting therapeutic efficiency by simultaneously interfering with two critical therapeutic resistance mechanisms.

A minimalist dendrimer nanodrug for autophagy inhibition-amplified tumor photothermo-immunotherapy

Development of a powerful photothermal agent to exert combinational photothermo-immunotherapy of tumors through autophagy inhibition remains challenging. Herein, we report an indocyanine green (ICG)-modified dendrimer nanomedicine formulation encapsulated with an autophagy inhibitor chloroquine (CQ) for synergistic autophagy inhibition-enhanced photothermo-immunotherapy. Poly(amidoamine) dendrimers of generation 5 (G5) were covalently conjugated with ICG, full acetylated to neutralize their remaining amine termini, and physically loaded with CQ. The created G5. NHAc-ICG/CQ (GIC) complexes display desired colloidal stability, cytocompatibility and photothermal conversion efficiency (39.7%), and can induce apoptosis and immunogenic cell death of cancer cells under laser irradiation in coordination with autophagy inhibition, thereby promoting maturation of dendritic cells and subsequent tumoral infiltration of activated CD4+/CD8+ T cells. The incorporated autophagy inhibitor CQ also enhances the antitumor efficacy through NF-κB pathway activation to remodel the tumor microenvironment through repolarization of the tumor-associated macrophages to anti-tumor M1 type. With the combination of programmed cell death ligand 1 antibody-elicited immune check-point blockade, the developed GIC nanodrug enables effective restriction of the growth of both primary and distal tumors with amplified antitumor immune response. The developed GIC nanodrug with the minimalist composition displays a promising translation potential for autophagy inhibition-enhanced photothermo-immunotherapy of different tumor types.

Chloroquine Intervenes Nephrotoxicity of Nilotinib through Deubiquitinase USP13-Mediated Stabilization of Bcl-XL.

Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin-proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.

Codelivery of vorinostat and chloroquine by autophagy-inhibitory hollow ZrO2 nanoshells for synergistic combination chemotherapy

Autophagy induction is responsible for the chemoresistance of histone deacetylase (HDAC) inhibitors. The combination of HDAC inhibitors with autophagy inhibitors has been considered a new strategy for treating solid tumors. However, codelivery systems capable of transporting these two kinds of drugs with different physicochemical properties and the simultaneous release of drugs remain elusive. In this study, hollow zirconium dioxide (ZrO2) nanoshells were synthesized to encapsulate both the autophagy inhibitor chloroquine (CQ) and the HDAC inhibitor vorinostat (Vor) for effective combinational cancer therapy. The ZrO2 nanoshells showed high loading capacities for both CQ and Vor due to the high affinity of ZrO2 for the phosphate and hydroxamic acid groups of the drugs, and the drug-loaded ZrO2 nanoshells exhibited a controlled release profile. The intrinsic autophagy inhibitory effect of the ZrO2 nanoshells enhanced the effect of either the single drug (CQ or Vor) or the combination of these two drugs. The codelivery system enhanced the autophagy inhibition and hyperacetylation level in the cells compared with free drugs, resulting in a superior antitumor effect in 4T1 tumor-bearing mice. Taken together, the multifunctional ZrO2 nanoshells hold great potential for the codelivery of HDAC and autophagy inhibitors for solid tumors therapy.