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Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment. [ABSTRACT FROM AUTHOR]

Malaria caused by Plasmodium protozoa, transmitted by the Anopheles mosquitoes' is one ofthe most important diseases. Current antimalarial drugs target vital parasite progressions ormetabolic pathways essential for parasitic development, thus aiding the host in overcomingthe infection by inhibiting protozoa growth. However, at the same time, it also produces adisruptive consequence on the host cells. These cause severe adverse effects on the host andlead to drug resistance. The urgent need for novel, non‐toxic anti‐protozoal compounds isevident due to the resistance developed against drugs like chloroquine andhydroxychloroquine. Metal complexes of various elements like iron, gold, ruthenium, and othershave shown their anti‐malarial potential. We have reviewed the research ongoing globally on the developments of new molecules of chloroquine coupled with different transition elements and describe the structure–activity relationship of chloroquine, which also provides insights into the chemistry of these compounds. [ABSTRACT FROM AUTHOR]

Pyruvate dehydrogenase kinase (PDK), which phosphorylates the pyruvate dehydrogenase complex, regulates glucose metabolism in skeletal muscle. PDK1, an isozyme whose expression is controlled by hypoxia-inducible factor-1α (HIF-1α), is thought to play a role in muscle adaptation to hypoxia. While transcriptional upregulation of PDK1 by HIF-1α is well characterised, mechanisms controlling proteolysis of PDK1 in skeletal muscle have not been thoroughly investigated. Proteasome inhibitor MG132 paradoxically reduced the abundance of PDK1 in human cancer cells and rat L6 myotubes, suggesting that MG132 might direct PDK1 towards autophagic degradation. The objectives of our current study were to determine (1) whether MG132 suppresses PDK1 levels in primary human myotubes, (2) whether chloroquine, an inhibitor of autophagy, prevents MG132-induced suppression of PDK1 in L6 myotubes, and (3) whether PYR-41, an inhibitor of ubiquitination, suppresses PDK1 in L6 myotubes. Using qPCR and/or immunoblotting, we found that despite markedly upregulating HIF-1α protein, MG132 did not alter the PDK1 expression in cultured primary human myotubes, while it suppressed both PDK1 mRNA and protein in L6 myotubes. The PDK1 levels in L6 myotubes were suppressed also during co-treatment with chloroquine and MG132. PYR-41 markedly increased the abundance of HIF-1α in primary human and L6 myotubes, while reducing the abundance of PDK1. In L6 myotubes treated with PYR-41, chloroquine increased the abundance of the epidermal growth factor receptor, but did not prevent the suppression of PDK1. Collectively, our results suggest that cultured myotubes degrade PDK1 via a pathway that cannot be inhibited by MG132, PYR-41, and/or chloroquine. [ABSTRACT FROM AUTHOR]

AbstractPurposeMethodsResultsConclusionAutophagy dysregulation triggers extracellular matrix remodeling via changes in cellular collagen levels and protease secretion. However, the effect of autophagy on scleral extracellular matrix remodeling in the context of myopia is not fully understood. In this study, we measured the level of autophagy in sclera of form deprivation myopic guinea pigs; we also sought a correlation between the level of autophagy in human scleral fibroblasts and the extent of COL1A1 synthesis.We measured the level of COL1A1 expression and the levels of autophagic protein markers in scleral tissues in vivo using a form deprivation myopic guinea pig model. Rapamycin and chloroquine were respectively used to activate and inhibit autophagy in cultured human scleral fibroblasts. COL1A1 gene and protein expression levels were analyzed via quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence. Levels of autophagy-related proteins were assessed via Western blotting.The sclera of form deprivation myopic guinea pig eyes exhibited decreased expression of COL1A1 and increased expression level of autophagy. After chloroquine exposure, human scleral fibroblasts exhibited decreased autophagy and increased COL1A1 expression.Inhibition of scleral fibroblast autophagy increased COL1A1 expression at the gene and protein levels, thus explaining the effect of autophagy on collagen synthesis by scleral fibroblasts. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood. Methods: To assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT–qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT–qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1's regulation of autophagy in GC. Results: Our findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo. Conclusion: PTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC. [ABSTRACT FROM AUTHOR]

This research introduces a novel electrochemical sensor designed for the detection of chloroquine. The sensor was developed via a simple method to synthesize TiO2 nanoparticles on reduced graphene oxide. The modified electrodes created in this manner exhibited high electrocatalytic activity and distinct chemical reactivity. Various techniques were utilized to perform morphological characterization of the nanocomposites. These techniques revealed alterations revealed changes in functional groups and the attachment of titanium to the reduced graphene oxide present on the electrode surface, thereby elucidating the reasons for the enhanced electrochemical performance. The sensor had a broad measurement range for chloroquine, capable of detecting concentrations as low as 10−8 M. It is applicable for diverse sample analyses, including water, pharmaceuticals, human urine, and serum, with satisfaction ranging between 97 and 99%. The development strategy. An electrochemical sensor was developed using titanium oxide nanoparticles attached to reduced graphene oxide TiO2-NPs @RGO/GCE for real-time detection of chloroquine in real contaminated samples such as human urine, human serum, and tap water with low detection limit. [ABSTRACT FROM AUTHOR]

The HSP70 co-chaperone BAG3 targets unfolded proteins to degradation via chaperone assisted selective autophagy (CASA), thereby playing pivotal roles in the proteostasis of adult cardiomyocytes (CMs). However, the complex functions of BAG3 for regulating autophagy in cardiac disease are not completely understood. Here, we demonstrate that conditional inactivation of Bag3 in murine CMs leads to age-dependent dysregulation of autophagy, associated with progressive cardiomyopathy. Surprisingly, Bag3 -deficient CMs show increased canonical and non-canonical autophagic flux in the juvenile period when first signs of cardiac dysfunction appear, but reduced autophagy during later stages of the disease. Juvenile Bag3 -deficient CMs are characterized by decreased levels of soluble proteins involved in synchronous contraction of the heart, including the gap junction protein Connexin 43 (CX43). Reiterative administration of chloroquine (CQ), an inhibitor of canonical and non-canonical autophagy, but not inactivation of Atg5 , restores normal concentrations of soluble cardiac proteins in juvenile Bag3 -deficient CMs without an increase of detergent-insoluble proteins, leading to complete recovery of early-stage cardiac dysfunction in Bag3 -deficient mice. We conclude that loss of Bag3 in CMs leads to age-dependent differences in autophagy and cardiac dysfunction. Increased non-canonical autophagic flux in the juvenile period removes soluble proteins involved in cardiac contraction, leading to early-stage cardiomyopathy, which is prevented by reiterative CQ treatment. [Display omitted] • Inactivation of Bag3 in CMs initiates hypertrophic cardiomyopathy in juvenile mice • Juvenile but not late stage Bag3 -deficient CMs show increased autophagic flux • Inactivation of Atg5 does not improve cardiac function in juvenile Bag3 -cKO mice • Treatment with chloroquine normalizes cardiac function in juvenile Bag3 -cKO mice • Human BAG3P209L heart samples show similar changes as in Bag3 -cKO mice [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effect of antimalarial drugs in response to therapy, incidence of LN flares, and progression of kidney disease in a large LN cohort. Methods We retrospectively studied 424 biopsy-proven LN patients followed for >3 years. We obtained demographic, clinical, laboratory, histopathological and treatment variables. Antimalarial use was approached as (i) users vs no users, (ii) according to prevalent vs incident use regarding the LN flare and (iii) according to the type of antimalarial. All outcomes were evaluated by time-to-event analyses. Adjusted hazard ratios were obtained by Cox regression. Results The cohort included 424 patients, median age of 29 years (IQR 23–37), 96% female, with a median eGFR of 81 ml/min/1.73 m2 (IQR 48–118) and proteinuria of 3.4 g/g (IQR 1.9–5.5). Antimalarial use was associated with higher complete response (aHR 1.57, 1.08–2.27), lower incidence of kidney flares (aHR 0.63, 0.43–0.92) and lower progression to kidney failure (aHR 0.37, 0.23–0.53). The effect of antimalarials on these outcomes was modified by the presentation eGFR, histological class and/or concomitant initial immunosuppressor. These protective effects were observed in patients with prevalent or incident use regarding the LN flare and patients using hydroxychloroquine. The incidence of toxic retinopathy was 1.7%, 5.7% and 8.8% by 3, 5 and 7 years of continued antimalarial use, respectively. Conclusion The use of antimalarial drugs is associated with increased response to therapy, lower incidence of kidney flares, and lower progression to kidney failure in LN patients. Conversely, this population is at high risk of toxic maculopathy, and yearly ophthalmologic examination is recommended. [ABSTRACT FROM AUTHOR]

Chloroquine (CQ) has been a good treatment for antimalarial mainstay for several decades; additionally discovered, it has a significant therapeutic impact on some instances of fungal inhibition. This study focused on the effect of novel CQ compounds on the activity of two different species of fungi, Aspergillus niger and Aspergillus falves. The activity of each CQ derivative was monitored using Nuclear magnetic resonance spectroscopy (NMR), minimal inhibitory concentration and physical parameters such as optical microscopy, UV/visible absorbance and optical band gap. NMR indicated the conjugation between the substrate and amino acid. The optical microscopic images indicated homogeneously distributed and uniform density distribution of CQ-derivative particles on the glass substrates. The samples' presented absorption peaks at 203, 207 and 220 nm wavelengths, suggesting the important electronic transition with reducing the indirect bandgap from 4.1 eV to 3.95 eV. These compounds have the best antifungal growth inhibitory properties and excellent features, indicating cosmetics use. [ABSTRACT FROM AUTHOR]

Simple Summary: Weaning stress is a critical factor contributing to diseases and even mortality in piglets during the weaning process. Research indicates that inhibition of intestinal autophagy to a certain extent can alleviate the decline in growth performance associated with weaning stress by enhancing the management of intestinal oxidative stress and inflammation. Interestingly, gut microbes serve an irreplaceable role in the regulation of autophagy. Therefore, we speculate that intestinal microbes may play a direct or indirect role in the process of intestinal autophagy inhibition, alleviating weaning stress in piglets. In this study, we utilized autophagy inhibitors (chloroquine, CQ) or activators (rapamycin, RAPA) to modulate the intestinal autophagy level in weaned piglets. We then investigated how changes in autophagy impacted the composition of intestinal microbes and their metabolites in these piglets, allowing us to explore the effects of autophagy from a microbial perspective. We found that the level of autophagy affected the composition of intestinal microbes and metabolites of weaned piglets, which may be one of the key factors in how autophagy alleviates weaning stress in piglets. Our findings also provide some insights to may guide the future application of autophagy inhibitors in piglets' diets. Our previous study demonstrated that moderate inhibition of intestinal autophagy was beneficial to alleviate early weaning stress in piglets, but the detailed mechanism behind this was unclear. Microbiota-mediated enterocyte autophagy helps maintain intestinal homeostasis. This study investigated the effects of inhibition or activation of autophagy in intestinal microbial community compositions and metabolite profiles in piglets. Eighteen 24-day-old weaned piglets were divided into three groups (each treatment of six piglets) and treated daily with rapamycin (RAPA), chloroquine (CQ) or a control volume of normal saline (CON group). Before the formal trial, the piglets were allowed to acclimatize for 3 days, and then the trial period was 14 days. Collected samples from the ileum and colon underwent 16S rRNA gene sequencing and metabolite analysis. Significant differences in microbial composition were observed in both the ileum and colon of the RAPA and CQ groups compared to the CON group (p < 0.05). In addition, the relative levels of abundance of Peptostreptococcus, Fusobacterium, Dialister, Selenomonas and Oceanobacillus in the ileum and Porphyromonas, Bacteroides, unidentified_Lachnospiraceae, Akkermansia, Sharpea, Peptococcus, Pseudoalteromonas, Peptoclostridium and unidentified_Acidobacteria in the colon were improved in piglets fed the RAPA diet, whereas the relative levels of abundance of Turicibacter, Rickettsiella and Sarcina in the ileum and Roseburia and Kroppenstedtia in the colon were enhanced in the CQ group (p < 0.05). Meanwhile, metabolomic analysis showed that there were significant differences in metabolites among all groups (p < 0.05), and KEGG enrichment analysis revealed that differential metabolites were mainly enriched in the ABC transporters and biosynthesis of amino acids pathways. Furthermore, these metabolites were closely related to differential microorganisms (p < 0.05). Overall, autophagy inhibition regulates the composition of intestinal microorganisms and their metabolites, and these differential metabolites are significantly correlated with differential intestinal microorganisms, which may in turn affect the production performance of weaned piglets. [ABSTRACT FROM AUTHOR]

Plasmodium vivax causes the largest malaria burden in Brazil, and chloroquine resistance poses a challenge to eliminating malaria by 2035. Illegal mining in the Roraima Yanomami Indigenous territory can lead to the introduction of resistant parasites. This study aimed to investigate mutations in the pvcrt-o and pvmdr-1 genes to determine their potential as predictors of P. vivax chloroquine-resistant phenotypes. Samples were collected in two health centers of Boa Vista. A questionnaire was completed, and blood was drawn from each patient. Then, DNA extraction, PCR, amplicon purification, and DNA sequencing were performed. After alignment with the Sal-1, the amplified fragment was analyzed. Patients infected with the mutant parasites were queried in the Surveillance Information System. Among the patients, 98% (157/164) of participants were from illegal mining areas. The pvcrt-o was sequenced in 151 samples, and the K10 insertion was identified in 13% of them. The pvmdr1 was sequenced in 80 samples, and the MYF haplotype (958M) was detected in 92% of them and the TYF was detected in 8%, while the MYL was absent. No cases of recrudescence, hospitalization, or death were found. Mutations in the pvcrt-o and pvmdr-1 genes have no potential to predict chloroquine resistance in P. vivax. [ABSTRACT FROM AUTHOR]

G‐protein‐coupled receptors (GPCRs) belonging to the type 2 taste receptors (TAS2Rs) family are predominantly present in taste cells to allow the perception of bitter‐tasting compounds. TAS2Rs have also been shown to be expressed in human airway smooth muscle (ASM), and TAS2R agonists relax ASM cells and bronchodilate airways despite elevating intracellular calcium. This calcium "paradox" (calcium mediates contraction by pro‐contractile Gq‐coupled GPCRs) and the mechanisms by which TAS2R agonists relax ASM remain poorly understood. To gain insight into pro‐relaxant mechanisms effected by TAS2Rs, we employed an unbiased phosphoproteomic approach involving dual‐mass spectrometry to determine differences in the phosphorylation of contractile‐related proteins in ASM following the stimulation of cells with TAS2R agonists, histamine (an agonist of the Gq‐coupled H1 histamine receptor) or isoproterenol (an agonist of the Gs‐coupled β2‐adrenoceptor) alone or in combination. Our study identified differential phosphorylation of proteins regulating contraction, including A‐kinase anchoring protein (AKAP)2, AKAP12, and RhoA guanine nucleotide exchange factor (ARHGEF)12. Subsequent signaling analyses revealed RhoA and the T853 residue on myosin light chain phosphatase (MYPT)1 as points of mechanistic divergence between TAS2R and Gs‐coupled GPCR pathways. Unlike Gs‐coupled receptor signaling, which inhibits histamine‐induced myosin light chain (MLC)20 phosphorylation via protein kinase A (PKA)‐dependent inhibition of intracellular calcium mobilization, HSP20 and ERK1/2 activity, TAS2Rs are shown to inhibit histamine‐induced pMLC20 via inhibition of RhoA activity and MYPT1 phosphorylation at the T853 residue. These findings provide insight into the TAS2R signaling in ASM by defining a distinct signaling mechanism modulating inhibition of pMLC20 to relax contracted ASM. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The interaction of chloroquine (CQ) with peptide-bonded-ethyl selenol and ethanethiol was experimentally and thermodynamically studied, indicating that CQ can bind to peptide-bonded active selenols through electrostatic interactions with a protonated triethylamine moiety, revealing a reasonable mechanism by which CQ inhibits thioredoxin reductase (TrxR) and significantly reduces oxidoreductase activity. [ABSTRACT FROM AUTHOR]

Copyright of Revista Foco (Interdisciplinary Studies Journal) is the property of Revista Foco and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Malaria continues to wreak havoc on the well-being of the community. Resistant parasites are jeopardizing the treatment. This is a wake-up call for better medications. Folk plants are the key starting point for antimalarial drug discovery. After crushing and mixing the leaves of Coriandrum sativum with water, one cup of tea is drunk daily for a duration of three to five days as a remedy for malaria by local folks in Ethiopia. Additionally, in vitro experiments conducted on the plant leaf extract elsewhere have also demonstrated the plant's malaria parasite inhibitory effect. There has been no pharmacologic research to assert this endowment in animals, though. This experiment was aimed at evaluating the antimalarial efficacy of C. sativum in Plasmodium berghei infected mice. Methods: The plant's leaf was extracted using maceration with distilled water. The extract was examined for potential acute toxicity. An evaluation of secondary phytoconstituents was done. Standard antimalarial screening models (prophylactic, chemosuppressive, curative tests) were utilized to assess the antiplasmodial effect. In each test, thirty mice were organized into groups of five. To the three categories, the test substance was given at doses of 100, 200 and 400 mg/kg/day before or after the commencement of P. berghei infection. Positive and negative control mice were provided Chloroquine and distilled water, respectively. Rectal temperature, parasitemia, body weight, survival time and packed cell volume were ultimately assessed. Analysis of the data was performed using Statistical Package for Social Sciences. Results: No toxicity was manifested in mice. The extract demonstrated a significant inhibition of parasitemia (p < 0.05) in all the models. The inhibition of parasite load was highest with the upper dose in the suppressive test (82.74%) followed by the curative procedure (78.49%). Likewise, inhibition of hypothermia, weight loss hampering, improved survival and protection against hemolysis were elicited by the extract. Conclusions: The results of our experimental study revealed that the aqueous crude leaf extract of C. sativum exhibits significant antimalarial efficacy in multiple in vivo models involving mice infected with P. berghei. Given this promising therapeutic attribute, in depth investigation on the plant is recommended. [ABSTRACT FROM AUTHOR]

Background: Plasmodium vivax malaria is still an important public health problem in Ethiopia. Unlike Plasmodium falciparum, P. vivax has a dormant liver stage (hypnozoite) that can be a risk of recurrent vivax malaria unless treated by radical cure with primaquine. Drug resistance to chloroquine is threatening malaria control and elimination efforts. This study assessed the therapeutic efficacy and safety of chloroquine plus 14 days of primaquine on P. vivax infection based on parasitological, clinical, and haematological parameters. Methods: A single-arm in vivo prospective therapeutic efficacy study was conducted to assess the clinical and parasitological response to the first-line treatment of P. vivax in Ethiopia, chloroquine plus 14 days low dose of (0.25 mg/kg/day) primaquine between December 2022 and March 2023 at Hamusit Health Centre using the standard World Health Organization (WHO) protocol. A total of 100 study participants with P. vivax mono-infection who were over 6 months old were enrolled and monitored for adequate clinical and parasitological responses for 42 days. The WHO double-entry Excel sheet and SPSS v.25 software were used for Kaplan–Meier survival analysis, and a paired t-test was used for analysis of haemoglobin improvements between follow up days. Results: A total of 100 patients were enrolled among those, 96% cases were rural residents, 93% had previous malaria exposure, and predominant age group was 5–15 years (61%). 92.6% (95% CI 85.1–96.4%) of enrolled patients were adequate clinical and parasitological response, and 7.4% (95% CI 3.6–14.9%) recurrences were observed among treated patients. The fever and parasite clearance rate on day 3 were 98% and 94%, respectively. The baseline haemoglobin levels improved significantly compared to those days 14 and 42 (p < 0.001). No serious adverse event was observed during the study period. Conclusions: In this study, co-administration of chloroquine with primaquine was efficacious and well-tolerated with fast resolution of fever and high parasites clearance rate. However, the 7.4% failure is reported is alarming that warrant further monitoring of the therapeutic efficacy study of P. vivax. [ABSTRACT FROM AUTHOR]

Malaria was a major cause of casualties during World War II in the Southwest Pacific, and drug supply issues were acute strategic concerns. The capture of the cinchona plantations of Indonesia by the Japanese Imperial Army and the lack of manufacturing capacity for synthetic substitutes were significant logistical constraints that limited Allied combat operations in the Indo-Pacific Region. Tens of thousands of soldiers were infected with malaria due to inadequate treatment and chemoprophylaxis. In Milne Bay, Papua New Guinea, military operations halted for several months at the end of 1942 due to poor malaria discipline compounded by inadequate medications. Sufficient drug supplies only became available in 1943 when daily quinacrine suppression was enforced. Drug supply disruptions during the COVID-19 pandemic are a reminder that specialist anti-infective medications could have an outsized, modern impact on military operations. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the high-quality literature on the frequency and nature of major adverse cardiac events (MACE) associated with either hydroxychloroquine (HCQ) or chloroquine (CQ). Data sources: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onward using search strategies created in collaboration with medical science librarians. Study selection and data extraction: Randomized controlled trials (RCTs) published in English language from January 1996 to September 2022, involving adult patients at least 18 years of age, were selected. Outcomes of interest were death, arrhythmias, syncope, and seizures. Random-effects meta-analyses were performed with a Treatment Arm Continuity Correction for single and double zero event studies. Data synthesis: By study drug, there were 31 HCQ RCTs (n = 6677), 9 CQ RCTs (n = 622), and 1 combined HCQ-CQ trial (n = 105). Mortality was the most commonly reported MACE at 220 of 255 events (86.3%), with no reports of torsades de pointes or sudden cardiac death. There was no increased risk of MACE with exposure to HCQ-CQ compared with control (risk ratio [RR] = 0.90, 95% CI = 0.69-1.17, I 2 = 0%). Relevance to patient care and clinical practice: These findings have important implications with respect to patient reassurance and updated guidance for prescribing practices of these medications. Conclusions: Despite listing as QT-prolonging meds, HCQ-CQ did not increase the risk of MACE. [ABSTRACT FROM AUTHOR]

Abstract Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment. Graphical abstract

Abstract Background Gastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood. Methods To assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT–qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT–qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1’s regulation of autophagy in GC. Results Our findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo. Conclusion PTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC. Graphical Abstract

The authors have advised there are errors in the Y-axis of Figures 1, 2 and 4 on pages 1097, 1099 and 1101, respectively. The Y-axis label “Body weight (kg)” in figure parts 1B, 2C and 4c should read “Body weight (g)”. The Y-axis label “Th2 cell counts (×103)” in figure parts 1G, 2H and 4H should read “Proportion of Th2 cells (%)”. The correct figures are as follows. Figure 1 Continued. Figure 1 CQ relieved MC903-induced type 2 inflammatory response in AD mice. (A) The severity of ear skin lesions; (B) dermatitis severity score; (C) left ear thickness; (D) H&E staining; (E) TB staining; (F) ELISA measurements of serum TSLP, IL-4, IL-13, IFN-γ, and IgE levels; (G) flow cytometry to determine the content of peripheral blood Th2 cells (CD3+CD4+CD193+). N = 6. Data were represented as mean ± standard deviation, one-way ANOVA was for data comparisons in panels A/D-G, with Tukey’s test serving for post hoc testing. ns represented P > 0.05, *P < 0.05, **P < 0.01, and ***P < 0.001. Two-way ANOVA was adopted in panels B-C, and Tukey’s multiple comparisons test was implemented for post hoc test. *Represented comparisons with the Control group, *P < 0.05, ***P < 0.001, #Represented comparisons with the AD group, #P < 0.05, ##P < 0.01. Figure 2 Continued. Figure 2 CQ abated type 2 inflammatory response in AD mice by inactivating TLR3. (A) Western blot detection of TLR3 protein expression; (B) the severity of ear skin lesions; (C) dermatitis severity score; (D) left ear thickness; (E) H&E staining; (F) TB staining; (G) ELISA detections of serum TSLP, IL-4, IL-13, IFN-γ, and IgE levels; (H) flow cytometry to assess the content of Th2 cells (CD3+CD4+CD193+). N = 6. Data were represented as mean ± standard deviation. Data in panel A were tested by one-way ANOVA, followed by post hoc testing using Tukey’s test. Two-way ANOVA was used for panels (C and D), and Šídák’s multiple comparisons test was used for post hoc test. Data in panels B/E-H were examined by independent sample t-test. ns represented P > 0.05, *P < 0.05, **P < 0.01, ***P < 0.001. Figure 4 Continued. Figure 4 Activation of NLRP3 partially averted the alleviating effect of CQ on type 2 inflammatory response in AD mice. (A) Western blot to test the expression levels of NLRP3, ASC and cleaved caspase-1 proteins; (B) the severity of ear skin lesions; (C) dermatitis severity score; (D) left ear thickness; (E) H&E staining; (F) TB staining; (G) ELISA detection of serum TSLP, IL-4, IL-13, IgE, IL-1β and IL-18 levels; (H) flow cytometry to assess the content of Th2 cells (CD3+CD4+CD193+). N = 6. Data were represented as mean ± standard deviation, and independent sample t-test was employed for comparisons in panels A-B/E-H. Two-way ANOVA was used in panels C-D, and Šídák’s multiple comparisons test was conducted for post hoc test. *P < 0.05, **P < 0.01. These corrections do not significantly impact the overall findings and conclusions of the paper. We would like to assure readers that the corrected values and labels do not alter the interpretations or validity of the research. The authors sincerely apologize for any confusion these errors may have caused.

Abstract Background Plasmodium vivax malaria is still an important public health problem in Ethiopia. Unlike Plasmodium falciparum, P. vivax has a dormant liver stage (hypnozoite) that can be a risk of recurrent vivax malaria unless treated by radical cure with primaquine. Drug resistance to chloroquine is threatening malaria control and elimination efforts. This study assessed the therapeutic efficacy and safety of chloroquine plus 14 days of primaquine on P. vivax infection based on parasitological, clinical, and haematological parameters. Methods A single-arm in vivo prospective therapeutic efficacy study was conducted to assess the clinical and parasitological response to the first-line treatment of P. vivax in Ethiopia, chloroquine plus 14 days low dose of (0.25 mg/kg/day) primaquine between December 2022 and March 2023 at Hamusit Health Centre using the standard World Health Organization (WHO) protocol. A total of 100 study participants with P. vivax mono-infection who were over 6 months old were enrolled and monitored for adequate clinical and parasitological responses for 42 days. The WHO double-entry Excel sheet and SPSS v.25 software were used for Kaplan–Meier survival analysis, and a paired t-test was used for analysis of haemoglobin improvements between follow up days. Results A total of 100 patients were enrolled among those, 96% cases were rural residents, 93% had previous malaria exposure, and predominant age group was 5–15 years (61%). 92.6% (95% CI 85.1–96.4%) of enrolled patients were adequate clinical and parasitological response, and 7.4% (95% CI 3.6–14.9%) recurrences were observed among treated patients. The fever and parasite clearance rate on day 3 were 98% and 94%, respectively. The baseline haemoglobin levels improved significantly compared to those days 14 and 42 (p

Yanqing Liu,1,&ast; Yuqing Meng,1,&ast; Junzhe Zhang,1 Liwei Gu,1 Shengnan Shen,1 Yongping Zhu,1 Jigang Wang1,2 1State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China; 2Department of Pharmacological Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore&ast;These authors contributed equally to this workCorrespondence: Jigang Wang; Yongping Zhu, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China, Email jgwang@icmm.ac.cn; ypzhu@icmm.ac.cnAbstract: Chloroquine is a common antimalarial drug and is listed in the World Health Organization Standard List of Essential Medicines because of its safety, low cost and ease of use. Besides its antimalarial property, chloroquine also was used in anti-inflammatory and antivirus, especially in antitumor therapy. A mount of data showed that chloroquine mainly relied on autophagy inhibition to exert its antitumor effects. However, recently, more and more researches have revealed that chloroquine acts through other mechanisms that are autophagy-independent. Nevertheless, the current reviews lacked a comprehensive summary of the antitumor mechanism and combined pharmacotherapy of chloroquine. So here we focused on the antitumor properties of chloroquine, summarized the pharmacological mechanisms of antitumor progression of chloroquine dependent or independent of autophagy inhibition. Moreover, we also discussed the side effects and possible application developments of chloroquine. This review provided a more systematic and cutting-edge knowledge involved in the anti-tumor mechanisms and combined pharmacotherapy of chloroquine in hope of carrying out more in-depth exploration of chloroquine and obtaining more clinical applications.Keywords: Chloroquine, pharmacology, applications, combined pharmacotherapy

Objective To evaluate the effects of chloroquine alone and in combination with traditional antifungal agents on the Candida albicans biofilms and its drug resistance. Methods This study used standard strains of Candida albicans, and drug-resistant strains of Candida albicans. The inhibitory effects of chloroquine alone and in combination with antifungal drugs on biofilms of Candida albicans were detected by XTT reduction method and chessboard dilution method respectively. The morphological characteristics of biofilms were observed under scanning electron microscopy. Results Chloroquine at the concentration of 50 μmol/L or above showed a direct inhibitory effect and increased with concentration. Chloroquine combined with amphotericin B had a synergistic inhibitory effect. Results of the time-killing curve showed that the growth trends of biofilms treated with chloroquine alone and combined with amphotericin B varied in different time periods during the experimental culture. Morphological observation also revealed that chloroquine alone and in combination with amphotericin B could reduce the ability of Candida albicans to form hyphae and biofilms. Conclusion Chloroquine has an inhibitory effect on Candida albicans biofilms and can reduce its drug resistance. Furthermore, chloroquine shows a synergistic anti-fungal effect when combined with amphotericin B.

Pharmaceutically active compounds are the most widely produced and consumed consumer products that pose a substantial threat to the environment and living organisms owing to their pharmacokinetics, side effects, and contraindications. In this study, the degradation of chloroquine (CQ), a popular antimalarial and recently proposed COVID-19 drug, was investigated under electron beam (EB) irradiation of aqueous solutions. Both the hydroxyl radical and hydrated electron generated in the radiolysis of water contribute to the degradation of CQ in aqueous solution. The overall removal efficiency for 125 mg·L-1 of the CQ solution under EB treatment is reported to be >80% at neutral pH at a maximum irradiation dose of 7 kGy. Removal efficiency is further favored by acidic and slightly alkaline conditions where reactions with hydroxyl radicals and hydrated electrons are favored, respectively. Additionally, increments in the applied dose resulted in the increased removal efficiency for the same concentration of CQ. Conversely, the removal efficiency decreased with increasing concentration of CQ at the same irradiation dose. The initial solution pH, applied irradiation dose, and initial pollutant concentration play an important role in the EB-induced degradation of CQ by influencing the available oxidizing and reducing species. The chemical oxygen demand (COD) and total organic carbon (TOC) were not significantly decreased during the treatment process and indicated the formation of organic byproducts, which were not further degraded under the current experimental conditions.

Abstract Background Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The first-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been local reports of CQ resistance. A clinical study was conducted to determine the efficacy of CQ for the treatment of P. vivax malaria in southern Ethiopia. Methods In 2021, patients with P. vivax mono-infection and uncomplicated malaria were enrolled and treated with 25 mg/kg CQ for 3 consecutive days. Patients were followed for 28 days according to WHO guidelines. The data were analysed using per-protocol (PP) and Kaplan‒Meier (K‒M) analyses to estimate the risk of recurrent P. vivax parasitaemia on day 28. Results A total of 88 patients were enrolled, 78 (88.6%) of whom completed the 28 days of follow-up. Overall, 76 (97.4%) patients had adequate clinical and parasitological responses, and two patients had late parasitological failures. The initial therapeutic response was rapid, with 100% clearance of asexual parasitaemia within 48 h. Conclusion Despite previous reports of declining chloroquine efficacy against P. vivax, CQ retains high therapeutic efficacy in southern Ethiopia, supporting the current national treatment guidelines. Ongoing clinical monitoring of CQ efficacy supported by advanced molecular methods is warranted to inform national surveillance and ensure optimal treatment guidelines.

Chloroquine (CQ) is a 4-aminoquinoline derivative largely employed in the management of malaria. CQ treatment exploits the drug's ability to cross the erythrocyte membrane, inhibiting heme polymerase in malarial trophozoites. Accumulation of CQ prevents the conversion of heme to hemozoin, causing its toxic buildup, thus blocking the survival of Plasmodium parasites. Recently, it has been reported that CQ is able to exert antiviral properties, mainly against HIV and SARS-CoV-2. This renewed interest in CQ treatment has led to the development of new studies which aim to explore its side effects and long-term outcome. Our study focuses on the effects of CQ in non-parasitized red blood cells (RBCs), investigating hemoglobin (Hb) functionality, the anion exchanger 1 (AE1) or band 3 protein, caspase 3 and protein tyrosine phosphatase 1B (PTP-1B) activity, intra and extracellular ATP levels, and the oxidative state of RBCs. Interestingly, CQ influences the functionality of both Hb and AE1, the main RBC proteins, affecting the properties of Hb oxygen affinity by shifting the conformational structure of the molecule towards the R state. The influence of CQ on AE1 flux leads to a rate variation of anion exchange, which begins at a concentration of 2.5 μM and reaches its maximum effect at 20 µM. Moreover, a significant decrease in intra and extracellular ATP levels was observed in RBCs pre-treated with 10 µM CQ vs. erythrocytes under normal conditions. This effect is related to the PTP-1B activity which is reduced in RBCs incubated with CQ. Despite these metabolic alterations to RBCs caused by exposure to CQ, no signs of variations in oxidative state or caspase 3 activation were recorded. Our results highlight the antithetical effects of CQ on the functionality and metabolism of RBCs, and encourage the development of new research to better understand the multiple potentiality of the drug. [ABSTRACT FROM AUTHOR]

Background Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The frst-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been local reports of CQ resistance. A clinical study was conducted to determine the efcacy of CQ for the treatment of P. vivax malaria in southern Ethiopia. Methods In 2021, patients with P. vivax mono-infection and uncomplicated malaria were enrolled and treated with 25 mg/kg CQ for 3 consecutive days. Patients were followed for 28 days according to WHO guidelines. The data were analysed using per-protocol (PP) and Kaplan‒Meier (K‒M) analyses to estimate the risk of recurrent P. vivax parasitaemia on day 28. Results A total of 88 patients were enrolled, 78 (88.6%) of whom completed the 28 days of follow-up. Overall, 76 (97.4%) patients had adequate clinical and parasitological responses, and two patients had late parasitological failures. The initial therapeutic response was rapid, with 100% clearance of asexual parasitaemia within 48 h. Conclusion Despite previous reports of declining chloroquine efcacy against P. vivax, CQ retains high therapeutic efcacy in southern Ethiopia, supporting the current national treatment guidelines. Ongoing clinical monitoring of CQ efcacy supported by advanced molecular methods is warranted to inform national surveillance and ensure optimal treatment guidelines. [ABSTRACT FROM AUTHOR]

Objective: Chloroquine (CQ) and hydroxychloroquine (HCQ) were used as off-label treatments for SARS-CoV-2 infection during the first pandemic waves. The urgency of combatting COVID-19 led to the dissemination of medical recommendations with a scarce awareness of possible drug–drug interactions. This issue primarily concerned people already taking multiple medications, such as older individuals. We estimated the prevalence of drug interactions with CQ or HCQ in COVID-19 inpatients during the first pandemic waves and their possible association with hospitalization-related outcomes. Methods: This study considers 487 patients aged ≥60, hospitalized for COVID-19 from March to December 2020, and treated with CQ or HCQ. Data on acute and chronic therapies and hospitalization length and outcomes were derived from medical records. The presence of drugs potentially interacting with CQ and HCQ was identified based on published literature and drug databases. Results: In our sample (mean age 77.1 years, 47.8% females), 255 (52.4%) patients presented with one drug interaction with CQ or HCQ, and 114 (23.4%) had more than two interactions. The most frequent drugs potentially interacting with CQ or HCQ were lopinavir/ritonavir (50.4%), azithromycin (47.2%), tocilizumab (15.4%), levofloxacin (8.7%), clarithromycin (6.0%), amlodipine (3.3%), and trazodone (2.4%). No substantial differences in the duration and outcomes of the hospitalization emerged as a function of the presence of drug–drug interactions. Conclusions: Many older patients prescribed with CQ or HCQ, which have lately proved ineffective against COVID-19, were exposed to the risk of drug–drug interaction. This underlines that medical recommendations should undergo careful peer review before being widely disseminated, even in emergencies like a pandemic. [ABSTRACT FROM AUTHOR]

BACKGROUND: In the present study, two structurally similar alkaloids from trees of Cinchona genus, chloroquine and cinchonine, were examined for their vasorelaxant effects in a model of phenylephrine-induced smooth muscle contractions. METHODS: Potential mechanisms of action associated with endothelial vasorelaxant compounds, voltage-gated Ca2+ channels (LTCCs), and inositol triphosphate receptors were examined in isolated rat aortic rings. Also, an in silico approach was used to predict the activity of the two test compounds. RESULTS: Experimental results revealed that both chloroquine and cinchonine significantly decrease phenylephrine-induced smooth muscle contractions, although to a different extent. Evaluated mechanisms of action indicate that endothelium is not involved in the vasorelaxant action of the two tested alkaloids. On the other hand, voltage-gated Ca2+ channels were found to be the dominant way of action associated with the vasorelaxant action of chloroquine and cinchonine. Finally, IP3R is found to have only a small impact on the observed activity of the tested compounds. CONCLUSION: Molecular docking studies predicted that chloroquine possesses a significant activity toward a suitable model of LTCCs, while cinchonine does not. The results of the present study point to the fact that great caution should be paid while administering chloroquine to vulnerable patients, especially those with cardiovascular disorders (Tab. 3, Fig. 3, Ref. 28). Text in PDF www.elis.sk [ABSTRACT FROM AUTHOR]

Purpose: Coronavirus disease 2019 (COVID-19) has affected millions of people worldwide and caused mortality. Many factors have been reported to affect the prognosis of COVID-19. In this study, we aimed to investigate the effects of drug therapy and vaccination on prognosis in patients hospitalized with a COVID-19 diagnosis. Methods: In this single-center, cross-sectional study, data were retrospectively collected from patients receiving inpatient treatment at a university hospital with a diagnosis of COVID-19 between January 1, 2020, and April 30, 2022. The patients' demographic and clinical characteristics were recorded. The Chi-square, Cox and logistic regression was performed, P < 0.05 was considered statistically significant. Results: Total 1723 patients (50.1% were men, mean age: 60.6 ± 16.90) who had not been vaccinated rate was 27.0% (> 3 doses: 45.7%). Mortality rate was 17.0%. Increasing age, male, a high Charlson Comorbidity Index (CCI), and no vaccination significantly increased mortality (P < 0.05). The mortality rate was significantly lower in the chloroquine treatment group than in the other treatment groups. Increasing age, male, and a high CCI were determined to be factors that significantly increased the length of hospital stay (LOHS). LOHS found to be significantly lower in the favipiravir or chloroquine groups compared to the remaining treatment groups (P < 0.001). Both mortality and the LOHS significantly differed according to AST, d-dimer, ferritin, and GFR. Conclusion: This study primarily investigated the effect of treatment and vaccination on the prognosis of COVID-19. This was determined to be prepared for another potential pandemic that may arise due to COVID-19. [ABSTRACT FROM AUTHOR]