Occurrence of antibiotics, hormones and PFAs in surface water from a Nile tilapia aquaculture facility in a Brazilian hydroelectric reservoir.

This study assessed the occurrence of five antibiotics, three hormones, caffeine, and long and short-chain perfluoroalkyl and polyfluoroalkyl substances (PFASs) in surface water and feedstuff samples obtained from aquaculture cages in Três Marias reservoir in Brazil. This is the first work to evaluate the presence of PFAS in surface water used for aquaculture in Brazil. Solid-phase extraction and low temperature partitioning extraction followed by liquid chromatography coupled to mass spectrometry (LC-MS) were performed to process and analyze surface water samples and feedstuff, respectively. The ecotoxicological risk quotient was calculated for target compounds detected in water. Ciprofloxacin and caffeine were detected in all surface water samples. Pharmaceutical drugs ranged from 0.7 ng L-1 (trimethoprim) to 389.2 ng L -1 (ß-estradiol). Estrone (10.24 ng g-1) and ß-estradiol (66.20 ng g-1) were also found in feedstuff. Four PFASs (PFOA, PFDoA, PFTeDA, and PFBS) were detected (9.40-15.2 µg L-1) at levels higher than reported in studies conducted worldwide. Ecotoxicological risk assessment indicated high risks for caffeine and PFOA, PFDoA, and PFTeDA with RQ values from 10 to 103. These findings reveal risks to biodiversity, ecosystem integrity and human health considering possible intake of these contaminants by fish consumption due to potential bioaccumulation of these substances. Hence, it is critical to conduct more studies in this direction in Brazil and other low and middle-low-income countries.

The absence of eosinophils is associated with early metastatic lesions in Leishmania amazonensis-infected mice.

BACKGROUND: Eosinophils are granulocytes that rapidly increase frequency in the bloodstream during helminthic infections and allergic responses. They are found in tissue infected by Leishmania during early disease, but their role during infection is not entirely understood. OBJECTIVES: We aim to compare the disease due to Leishmania amazonensis in BALB/c and Δdbl-GATA1 mice, which lack eosinophils. METHODS: BALB/c and Δdbl-GATA1 mice infected with L. amazonensis were observed for several weeks. The parasite load and dissemination pattern were assessed. FINDINGS: The Δdbl-GATA1 mice developed an anticipated dissemination of L. amazonensis and a worsening disease. No differences were found in the lesion development or the parasite load in the footpad among Δdbl-GATA1 mice and BALB/c eight weeks after infection. However, nine weeks after infection, massive growth of metastatic lesions appeared in several parts of the skin in Δdbl-GATA1 mice, weeks earlier than BALB/c. We observed increased parasites in the bloodstream, probably an essential dissemination route. Thirteen weeks after infection, metastatic lesions were found in all Δdbl-GATA1 mice. MAIN CONCLUSION: These results suggest a protective role of eosinophils in delaying the disease caused by L. amazonensis, although several limitations of this mice strain must be considered.

Preclinical evaluation of L-fucoside from lapachol-loaded nanoemulsion as a strategy to breast cancer treatment.

Breast cancer prevails as the most common cancer in women, underscoring an urgent need for more effective therapies. This study explores the potential of our newly developed nanoemulsion containing a novel fucoside derivative of lapachol (NE-F-LapA) as an intravenous treatment strategy. We sought to overcome the solubility issues associated with fucoside with this improved drug delivery strategy that enhances tumor delivery and mitigates other dose-limiting toxicities. Nanoemulsion was prepared and characterized by DLS, zeta potential, encapsulation efficiency, and storage stability. Cytotoxicity against breast cancer cell lines (4T1 and MDA-MB-231) and non-tumor human fibroblasts (NTHF) were evaluated. In vivo assays included antitumoral activity performance and acute systemic toxicity in mice models. NE-F-LapA was synthesized and optimized to 200 nm size, - 20 mV zeta potential, and near-complete (>98%) drug encapsulation. Stability exceeded 6 months, and biological fluid exposure maintained suitable properties for administration. In vitro, NE-F-LapA showed high toxicity (3 µM) against 4T1 and MDA-MB-231, enhanced five times the breast cancer cell uptake and three times the selectivity when compared to normal cells. Systemic toxicity assessment in mice revealed no concerning hematological or biochemical changes. Finally, in a 4T1 breast tumor model, NE-F-LapA significantly inhibited growth by 50% of the subcutaneous 4T1 tumor and reduced lung metastases 5-fold versus control. Overall, tailored nanoemulsification of the lapachol derivative enabled effective intravenous administration and improved efficacy over the free drug, indicating promise for enhanced breast cancer therapy pending further optimization.

The absence of eosinophils is associated with early metastatic lesions in Leishmania amazonensis-infected mice

BACKGROUND Eosinophils are granulocytes that rapidly increase frequency in the bloodstream during helminthic infections and allergic responses. They are found in tissue infected by Leishmania during early disease, but their role during infection is not entirely understood. OBJECTIVES We aim to compare the disease due to Leishmania amazonensis in BALB/c and Δdbl-GATA1 mice, which lack eosinophils. METHODS BALB/c and Δdbl-GATA1 mice infected with L. amazonensis were observed for several weeks. The parasite load and dissemination pattern were assessed. FINDINGS The Δdbl-GATA1 mice developed an anticipated dissemination of L. amazonensis and a worsening disease. No differences were found in the lesion development or the parasite load in the footpad among Δdbl-GATA1 mice and BALB/c eight weeks after infection. However, nine weeks after infection, massive growth of metastatic lesions appeared in several parts of the skin in Δdbl-GATA1 mice, weeks earlier than BALB/c. We observed increased parasites in the bloodstream, probably an essential dissemination route. Thirteen weeks after infection, metastatic lesions were found in all Δdbl-GATA1 mice. MAIN CONCLUSION These results suggest a protective role of eosinophils in delaying the disease caused by L. amazonensis, although several limitations of this mice strain must be considered.

In Vitro and Preclinical Antitumor Evaluation of Doxorubicin Liposomes Coated with a Cholesterol-Based Trimeric ß-D-Glucopyranosyltriazole.

The coating of liposomes with polyethyleneglycol (PEG) has been extensively discussed over the years as a strategy for enhancing the in vivo and in vitro stability of nanostructures, including doxorubicin-loaded liposomes. However, studies have shown some important disadvantages of the PEG molecule as a long-circulation agent, including the immunogenic role of PEG, which limits its clinical use in repeated doses. In this context, hydrophilic molecules as carbohydrates have been proposed as an alternative to coating liposomes. Thus, this work studied the cytotoxicity and preclinical antitumor activity of liposomes coated with a glycosyl triazole glucose (GlcL-DOX) derivative as a potential strategy against breast cancer. The glucose-coating of liposomes enhanced the storage stability compared to PEG-coated liposomes, with the suitable retention of DOX encapsulation. The antitumor activity, using a 4T1 breast cancer mouse model, shows that GlcL-DOX controlled the tumor growth in 58.5% versus 35.3% for PEG-coated liposomes (PegL-DOX). Additionally, in the preliminary analysis of the GlcL-DOX systemic toxicity, the glucose-coating liposomes reduced the body weight loss and hepatotoxicity compared to other DOX-treated groups. Therefore, GlcL-DOX could be a promising alternative for treating breast tumors. Further studies are required to elucidate the complete GlcL-DOX safety profile.

Nuclear factor kappa B expression in non-small cell lung cancer.

In this mini-review, we discuss the role of NF-κB, a proinflammatory transcription factor, in the expression of genes involved in inflammation, proliferation, and apoptosis pathways, and link it with prognosis of various human cancers, particularly non-small cell lung cancer (NSCLC). We and others have shown that NF-κB activity can be impacted by post-translational S-glutathionylation through reversible formation of a mixed disulfide bond between its cysteine residues and glutathione (GSH). Clinical data analysis showed that high expression of NF-κB correlated with shorter overall survival (OS) in NSCLC patients, suggesting a tumor promotion function for NF-κB. Moreover, NF-κB expression was associated with tumor stage, lymph node metastasis, and 5-year OS in these patients. NF-κB was over-expressed in the cytoplasm of tumor tissue compared to adjacent normal tissues. S-glutathionylation of NF-κB caused negative regulation by interfering with DNA binding activities of NF-κB subunits. In response to oxidants, S-glutathionylation of NF-κB also correlated with enhanced lung inflammation. Thus, S-glutathionylation is an important contributor to NF-κB regulation and clinical results highlight the importance of NF-κB in NSCLC, where NF-κB levels are associated with unfavorable prognosis.

Evaluation of acute toxicity and in vitro antitumor activity of a novel doxorubicin-loaded folate-coated pH-sensitive liposome.

Doxorubicin (DOX) loaded liposomes have been used and studied in the last decades due to the significant decrease in DOX induced cardiac and systemic toxicity relative to administration of free drug. Therefore, new strategies are sought to improve DOX delivery and antitumor activity, while avoiding side effects. Recently, folate-coated pH-sensitive liposomes (SpHL-Fol) have been studied as a tool to enhance cellular uptake and antitumor activity of paclitaxel and DOX in breast cancer cells expressing folate receptor (FR+). However, the elucidation of folate functionalization relevance in DOX-loaded SpHL (SpHL-DOX-Fol) in different cell types (MDA-MB-231, MCF-7, and A549), as well as, the complete safety evaluation, is necessary. To achieve these objectives, SpHL-DOX-Fol was prepared and characterized as previously described. Antitumor activity and acute toxicity were evaluated in vivo through direct comparison of free DOX verses SpHL-DOX, a well-known formulation to reduce DOX cardiotoxicity. The obtained data are crucial to support future translational research. Liposomes showed long-term stability, suitable for biological use. Cellular uptake, cytotoxicity, and percentage of migration inhibition were significantly higher for MDA-MB-231 (FR+) treated with SpHL-DOX-Fol. In addition, SpHL-DOX-Fol demonstrated a decrease in the systemic toxic effects of DOX, mainly in renal and cardiac parameters evaluation, even using a higher dose (20 mg/kg). Collectively these data build the foundation of support demonstrating that SpHL-DOX-Fol could be considered a promising drug delivery strategy for the treatment of FR+ breast tumors.

Toxins from Animal Venoms as a Potential Source of Antimalarials: A Comprehensive Review.

Malaria is an infectious disease caused by Plasmodium spp. and it is mainly transmitted to humans by female mosquitoes of the genus Anopheles. Malaria is an important global public health problem due to its high rates of morbidity and mortality. At present, drug therapies and vector control with insecticides are respectively the most commonly used methods for the treatment and control of malaria. However, several studies have shown the resistance of Plasmodium to drugs that are recommended for the treatment of malaria. In view of this, it is necessary to carry out studies to discover new antimalarial molecules as lead compounds for the development of new medicines. In this sense, in the last few decades, animal venoms have attracted attention as a potential source for new antimalarial molecules. Therefore, the aim of this review was to summarize animal venom toxins with antimalarial activity found in the literature. From this research, 50 isolated substances, 4 venom fractions and 7 venom extracts from animals such as anurans, spiders, scorpions, snakes, and bees were identified. These toxins act as inhibitors at different key points in the biological cycle of Plasmodium and may be important in the context of the resistance of Plasmodium to currently available antimalarial drugs.

Alpha-tocopheryl succinate and doxorubicin-loaded liposomes improve drug uptake and tumor accumulation in a murine breast tumor model.

Liposomes composed of a rigid bilayer have high plasma stability; however, they can be challenged in efficacy due to complications in releasing the encapsulated drug as well as being internalized by the tumor cell. On the other hand, fusogenic liposomes may fuse with the plasmatic membrane and release encapsulated material directly into the cytoplasm. In a previous study, fusogenic liposomes composed of alpha-tocopheryl succinate (TS) and doxorubicin (DOX) were developed (pHSL-TS-DOX). These stabilized tumor growth and reduced toxicity compared to a commercial formulation. In the present study, we investigated whether cellular uptake or DOX accumulation in the tumor could justify the better performance of the pHSL-TS-DOX formulation. Release, deformability, and DOX plasmatic concentration studies were also carried out. pHSL-TS-DOX showed an adequate release profile and demonstrated characteristics of a deformable formulation. Data from apoptosis, cell cycle, and nuclear morphology studies have shown that the induction of cell death caused by pHSL-TS-DOX occurred more quickly. Higher DOX cellular uptake and tumor accumulation were observed when pHSL-TS-DOX was administered, demonstrating better drug delivery capacity. Therefore, better DOX uptake as well as tumor accumulation explain the great antitumor activity previously demonstrated for this formulation.

East Timor as an important source of cashew (Anacardium occidentale L.) genetic diversity.

Background: Cashew (Anacardium occidentale L.) is a crop currently grown in several tropical countries because of the economic importance of cashew nuts. Despite its enormous economic worth, limited research has been conducted on the molecular diversity of cashew genetic resources. In this study, a wide comprehensive assessment of the genetic diversity of cashew trees in East Timor was performed using microsatellites (SSRs) to evaluate intraspecific diversity and population structuring. Methods: A total of 207 individual cashew trees, including trees from East Timor (11), and outgroup populations from Indonesia (one) and Mozambique (two), were analyzed with 16 cashew-specific SSRs. A comprehensive sampling of cashew trees within East Timor was performed, covering the distribution of cashew orchards in the country. Genetic diversity indices were calculated, and population structuring was determined using three different approaches: genetic distances (UPGMA and NJ), AMOVA, and individual-based clustering methods through Bayesian (STRUCTURE) and multivariate (DAPC) analyses. Results: The population structuring analysis revealed that the genetic diversity of cashew populations in East Timor was higher in this study than previously reported for cashew trees. A higher allelic richness was found within cashew populations in East Timor compared with the outgroup populations (Mozambique and Indonesia), reinforced by the presence of private alleles. Moreover, our study showed that cashew populations in East Timor are grouped into two dissimilar genetic groups, which may suggest multiple cashew introductions over time. These new cashew genetic resources could be explored for future crop improvement. Conclusions: Crop diversity underpins the productivity, resilience, and adaptive capacity of agriculture. Therefore, this study provides useful information regarding genetic diversity and population structure that can be harnessed to improve cashew production in East Timor. This data is also important to creating a country-specific genetic cashew signature to increase cashew market value.

Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis.

OBJECTIVE: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. METHODS: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. RESULTS: ADAM17adipoq-creΔ/Δ mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues, that acts to inhibit adipocyte differentiation and dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to repress the expression of genes involved in adipogenesis, thermogenesis, and lipid uptake, storage and catabolism. CONCLUSIONS: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that modulates energy balance in adipocytes by inhibiting adipocyte differentiation, thermogenesis and lipid catabolism.

Emetic Tartar-Loaded Liposomes as a New Strategy for Leishmaniasis Treatment.

Emetic tartar (ET), was used in the treatment of leishmaniasis but its use was discontinued due to its low therapeutic index. Liposomes have been shown to be a promising strategy for delivery of bioactive substances in the region of interest, in order to reduce and/or eliminate undesirable effects. In the present study, liposomes containing ET were prepared and characterized to evaluate acute toxicity as well as their leishmanicidal action using BALB/c mice with an inoculum of Leishmania (Leishmania) infantum. Liposomes were composed of egg phosphatidylcholine and 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol, with an average diameter of 200 nm, zeta potential of +18 mV, and ET encapsulated into liposomes at a concentration near 2 g/L. Healthy mice were treated with ET or liposome containing ET (Lip-ET) in a single dose of 16 mg/kg of Sb3+ intravenously and observed for 14 days. The death of two animals in the ET-treated group and no deaths in the Lip-ET-treated group was observed. Higher hepatic and cardiac toxicity were observed in animals treated with ET when compared to animals treated with Lip-ET, blank liposomes (Blank-Lip) and PBS. The study of antileishmanial efficacy was conducted by intraperitoneal administration of Lip-ET, for ten consecutive days. It was observed by limiting dilution that treatments with liposomal formulations containing ET, as well as Glucantime®, led to a significant reduction in parasitic load in spleen and liver (p < 0.05) when compared to the untreated control group.

Co-Encapsulation of Simvastatin and Doxorubicin into pH-Sensitive Liposomes Enhances Antitumoral Activity in Breast Cancer Cell Lines.

Doxorubicin (DOX) is a potent chemotherapeutic drug used as the first line in breast cancer treatment; however, cardiotoxicity is the main drawback of the therapy. Preclinical studies evidenced that the association of simvastatin (SIM) with DOX leads to a better prognosis with reduced side effects and deaths. In this work, a novel pH-sensitive liposomal formulation capable of co-encapsulating DOX and SIM at different molar ratios was investigated for its potential in breast tumor treatment. Studies on physicochemical characterization of the liposomal formulations were carried out. The cytotoxic effects of DOX, SIM, and their combinations at different molar ratios (1:1; 1:2 and 2:1), free or co-encapsulated into pH-sensitive liposomes, were evaluated against three human breast cancer cell lines (MDA-MB-231, MCF-7, and SK-BR-3). Experimental protocols included cell viability, combination index, nuclear morphological changes, and migration capacity. The formulations showed a mean diameter of less than 200 nm, with a polydispersity index lower than 0.3. The encapsulation content was ~100% and ~70% for DOX and SIM, respectively. A more pronounced inhibitory effect on breast cancer cell lines was observed at a DOX:SIM molar ratio of 2:1 in both free and encapsulated drugs. Furthermore, the 2:1 ratio showed synergistic combination rates for all concentrations of cell inhibition analyzed (50, 75, and 90%). The results demonstrated the promising potential of the co-encapsulated liposome for breast tumor treatment.

Cisplatin-Loaded Thermosensitive Liposomes Functionalized with Hyaluronic Acid: Cytotoxicity and In Vivo Acute Toxicity Evaluation.

Cisplatin (CDDP) is a potent antitumor drug used in first-line chemotherapy against several solid tumors, including breast cancer. However, toxicities and drug resistance limit its clinical application. Thermosensitive liposome (TSL) functionalized with hyaluronic acid (HA) containing cisplatin (TSL-CDDP-HA) was developed by our research group aiming to promote the release of CDDP in the tumor region under hyperthermia conditions, as well as to decrease toxicity. Thus, this study aimed to evaluate this new formulation (HA-coated TSL-CDDP) concerning in vitro behavior and in vivo toxicity compared to non-coated TSL-CDDP and free CDDP. Cytotoxicity assays and nuclear morphology were carried out against triple-negative breast cancer cells (MDA-MB-231), while an in vivo toxicity study was performed using healthy Swiss mice. The results showed an increase (around 3-fold) in cytotoxicity of the cationic formulation (non-coated TSL-CDDP) compared to free CDDP. On the other hand, TSL-CDDP treatment induced the appearance of 2.5-fold more senescent cells with alteration of nuclear morphology than the free drug after hyperthermia condition. Furthermore, the association of liposomal formulations treatment with hyperthermia increased the percentage of apoptotic cells compared to those without heating. The percentage of apoptotic cells was 1.7-fold higher for TSL-CDDP-HA than for TSL-CDDP. For the in vivo toxicity data, the TSL-CDDP treatment was also toxic to healthy cells, inducing nephrotoxicity with a significant increase in urea levels compared to the saline control group (73.1 ± 2.4 vs. 49.2 ± 2.8 mg/mL). On the other hand, the HA-coated TSL-CDDP eliminated the damages related to the use of CDDP since the animals did not show changes in hematological and biochemical examinations and histological analyses. Thus, data suggest that this new formulation is a potential candidate for the intravenous therapy of solid tumors.

The atheroprotective role of fucoidan involves the reduction of foam cell formation by altering cholesterol flux-associated factors in macrophages.

Atherosclerosis is characterized by the accumulation of lipid-laden cells in the arterial walls, resulting from dysregulation of cholesterol homeostasis in the macrophage, triggered by oxidized low-density lipoprotein (oxLDL). Previous studies have shown that fucoidan, a sulfated polysaccharide from brown seaweeds, has several atheroprotective activities, however, the mechanism of fucoidan protection is not fully understood. Thus, we investigated the effect of fucoidan on atherogenesis in apolipoprotein E-deficient (ApoE-/-) mice, on oxLDL uptake by macrophages, and on the expression of the flux-associated scavenger receptors by macrophages. Also, we examined the absorption and biodistribution of orally administered fucoidan. ApoE-/- mice fed on a cholesterol-rich diet supplemented with 1% fucoidan showed reduced dyslipidemia and atherosclerosis. Fucoidan was detected in blood and peripheral tissue after gavage, suggesting that it can exert direct systemic effects. In vitro, fucoidan reduced macrophage oxLDL uptake, which resulted in lower foam cell formation. This effect was associated with downregulation of the cholesterol influx-associated scavenger receptor (SR)-A expression, and upregulation of the cholesterol efflux-associated SR-B1 expression. In conclusion, fucoidan prevented oxLDL-mediated foam cell formation in macrophages by downregulating SR-A1/2 and by up-regulating SR-B1.

Clinical acute presentation of lumbar facet joint ganglia with bilateral sciatica / Apresentação clínica aguda de quistos facetários lombares com ciatalgia bilateral / Presentación clinica aguda de quistes facetarios lumbares con dolor ciático bilateral

ABSTRACT Facet joint ganglia are benign cystic lesions located adjacent to a facet joint. The majority is asymptomatic. However, can cause important low-back pain and radiculopathy. Neurogenic deficit, claudication, and cauda equina syndrome have also been reported. The authors report two cases of acute low back pain with bilateral sciatica, dorsal foot dysesthesia, and hallux dorsiflexion/extension deficit, due to the presence of encapsulated cysts adjacent to the facet joints causing a significant reduction of the spinal canal. Urgent surgical decompression was performed in both patients with an uneventful recovery. Symptomatic facet joint ganglia is a highly unusual cause of back pain, although it can present with acute onset of bilateral sciatica and canal stenosis requiring urgent surgical decompression. This paper highlights facet joint synovial as a differential diagnosis of lumbar pain and describes two different surgical approaches with good outcomes. Level of Evidence IV; Case Series.

RESUMO: Os quistos facetários são lesões císticas benignas localizadas adjacentes a uma articulação facetária. A maioria é assintomática. No entanto, podem ser causa de importante dor lombar e radiculopatia. Estão ainda relatados casos de déficit neurogénico, claudicação e síndrome de cauda equina. Os autores apresentam dois casos de dor lombar aguda com ciatalgia bilateral, disestesia do dorso do pé e défice na dorsiflexão/extensão do hálux, causados por uma redução significativa do canal medular devido à presença de quistos encapsulados adjacentes às articulações facetarias. Os doentes foram submetidos a descompressão cirúrgica urgente com uma excelente recuperação. Os quistos facetários sintomáticas são uma causa rara de lombalgia, porém podem apresentar-se inicialmente com um quadro agudo de ciatalgia bilateral e estenose canalar com necessidade de descompressão cirúrgica urgente. Este artigo realça os quistos facetários como diagnóstico diferencial de lombalgia e descreve duas abordagens cirúrgicas diferentes com bons resultados. Nível de Evidência IV; Série de Casos.

RESUMEN: Los quistes facetarios son lesiones quísticas benignas situadas junto a una articulación facetaria. La mayoría es asintomática. Pero pueden causar dolor lumbar y radiculopatía importantes. También se han descrito déficit neurogénico, claudicación y síndrome de cauda equina. Los autores presentan dos casos de lumbalgia aguda con dolor ciático bilateral, disestesia del dorso del pie y déficit en la dorsiflexión/extensión del hallux, causados por una reducción significativa del canal medular debido a la presencia de quistes encapsulados adyacentes a las articulaciones facetarias. Los pacientes fueron sometidos a descompresión quirúrgica urgente con una excelente recuperación. Los quistes facetarios sintomáticos son una causa poco frecuente de lumbalgia, aunque pueden presentarse inicialmente con un cuadro agudo de dolor ciático bilateral y estenosis del canal que requiere descompresión quirúrgica urgente. Este artículo destaca los quistes facetarios como diagnóstico diferencial de la lumbalgia y describe dos abordajes quirúrgicos diferentes con buenos resultados. Nivel de Evidencia IV; Serie de Casos.

DNA damage independent inhibition of NF-κB transcription by anthracyclines.

Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-κB subunit RelA and its DNA-binding sites. The anthracycline variants Aclarubicin, Doxorubicinone, and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.

Investigation of the Antitumor Activity and Toxicity of Tumor-Derived Exosomes Fused with Long-Circulating and pH-Sensitive Liposomes Containing Doxorubicin.

Exosome-liposome hybrid nanocarriers containing chemotherapeutic agents have been developed to enhance drug delivery, improve the efficacy of the treatment of metastatic cancer, and overcome chemoresistance in cancer therapy. Thus, the objectives of this study were to investigate the toxicological profiles of exosomes fused with long-circulating and pH-sensitive liposomes containing doxorubicin (ExoSpHL-DOX) in healthy mice and the antitumor activity of ExoSpHL-DOX in Balb/c female mice bearing 4T1 breast tumors. The acute toxicity was determined by evaluating the mortality and morbidity of the animals and conducting hematological, biochemical, and histopathological analyses after a single intravenous administration of ExoSpHL-DOX. The results of the study indicated that the ExoSpHL-DOX treatment is less toxic than the free doxorubicin (DOX) treatment. ExoSpHL-DOX showed no signs of nephrotoxicity, even at the highest dose of DOX, indicating that the hybrid nanosystem may alter the distribution of DOX and reduce the kidney damage. Regarding the antitumor activity, ExoSpHL-DOX showed an antitumor effect compared to the control group. Furthermore, the hybrid nanocarrier of tumor-derived exosomes fused with long-circulating and pH-sensitive liposomes reduced the number of metastatic foci in the lungs. These results indicate that ExoSpHL-DOX may be a promising nanocarrier for the treatment of breast cancer, reducing toxicity and inhibiting metastasis, mainly in the lungs.

Current Applications of Plant-Based Drug Delivery Nano Systems for Leishmaniasis Treatment.

Leishmania is a trypanosomatid that causes leishmaniasis. It is transmitted to vertebrate hosts during the blood meal of phlebotomine sandflies. The clinical manifestations of the disease are associated with several factors, such as the Leishmania species, virulence and pathogenicity, the host-parasite relationship, and the host's immune system. Although its causative agents have been known and studied for decades, there have been few advances in the chemotherapy of leishmaniasis. The urgency of more selective and less toxic alternatives for the treatment of leishmaniasis leads to research focused on the study of new pharmaceuticals, improvement of existing drugs, and new routes of drug administration. Natural resources of plant origin are promising sources of bioactive substances, and the use of ethnopharmacology and folk medicine leads to interest in studying new medications from phytocomplexes. However, the intrinsic low water solubility of plant derivatives is an obstacle to developing a therapeutic product. Nanotechnology could help overcome these obstacles by improving the availability of common substances in water. To contribute to this scenario, this article provides a review of nanocarriers developed for delivering plant-extracted compounds to treat clinical forms of leishmaniasis and critically analyzing them and pointing out the future perspectives for their application.

In Vitro and In Vivo Effect of pH-Sensitive PLGA-TPGS-Based Hybrid Nanoparticles Loaded with Doxorubicin for Breast Cancer Therapy.

Doxorubicin (DOX) is an antineoplastic agent clinically employed for treating breast cancer patients. Despite its effectiveness, its inherent adverse toxic side effects often limit its clinical application. To overcome these drawbacks, lipid-polymer hybrid nanoparticles (LPNP) arise as promising nanoplatforms that combine the advantages of both liposomes and polymeric nanoparticles into a single delivery system. Alpha-tocopherol succinate (TS) is a derivative of vitamin E that shows potent anticancer mechanisms, and it is an interesting approach as adjuvant. In this study, we designed a pH-sensitive PLGA-polymer-core/TPGS-lipid-shell hybrid nanoparticle, loaded with DOX and TS (LPNP_TS-DOX). Nanoparticles were physicochemically and morphologically characterized. Cytotoxicity studies, migration assay, and cellular uptake were performed in 4T1, MCF-7, and MDA-MB-231 cell lines. Antitumor activity in vivo was evaluated in 4T1 breast tumor-bearing mice. In vitro studies showed a significant reduction in cell viability, cell migration, and an increase in cellular uptake for the 4T1 cell line compared to free DOX. In vivo antitumor activity showed that LPNP-TS-DOX was more effective in controlling tumor growth than other treatments. The high cellular internalization and the pH-triggered payload release of DOX lead to the increased accumulation of the drugs in the tumor area, along with the synergic combination with TS, culminating in greater antitumor efficacy. These data support LPNP-TS-DOX as a promising drug delivery system for breast cancer treatment.