Efficacy and Security of Tetrodotoxin in the Treatment of Cancer-Related Pain: Systematic Review and Meta-Analysis

The pharmacological treatment of cancer-related pain is unsatisfactory. Tetrodotoxin (TTX) has shown analgesia in preclinical models and clinical trials, but its clinical efficacy and safety have not been quantified. For this reason, our aim was to perform a systematic review and meta-analysis of the clinical evidence that was available. A systematic literature search was conducted in four electronic databases (Medline, Web of Science, Scopus, and ClinicalTrials.gov) up to 1 March 2023 in order to identify published clinical studies evaluating the efficacy and security of TTX in patients with cancer-related pain, including chemotherapy-induced neuropathic pain. Five articles were selected, three of which were randomized controlled trials (RCTs). The number of responders to the primary outcome (≥30% improvement in the mean pain intensity) and those suffering adverse events in the intervention and placebo groups were used to calculate effect sizes using the log odds ratio. The meta-analysis showed that TTX significantly increased the number of responders (mean = 0.68; 95% CI: 0.19–1.16, p = 0.0065) and the number of patients suffering non-severe adverse events (mean = 1.13; 95% CI: 0.31–1.95, p = 0.0068). However, TTX did not increase the risk of suffering serious adverse events (mean = 0.75; 95% CI: −0.43–1.93, p = 0.2154). In conclusion, TTX showed robust analgesic efficacy but also increased the risk of suffering non-severe adverse events. These results should be confirmed in further clinical trials with higher numbers of patients.CTS-109 grant (Junta de Andalucía)FPU grant (FPU21/02736

Evidence of rare earth elements origin in acid mine drainage from the Iberian Pyrite Belt (SW Spain)

Acid mine drainage (AMD) is a worldwide pollution problem of watersheds. In addition to toxic metal(oid)s and acidity, many elements of economic interest are released into the environment, which make AMD a potential strategic secondary source of these elements such as rare earth elements (REE). Despite the importance of these metals, their origin in AMD is still uncertain. Recent hypotheses suggest preferential leaching of REE-enriched minerals as a possible source. Leaching tests with H2SO4 have been developed to simulate the interaction under AMD formation conditions with sulfide bodies and host rocks from two representative mining areas in the Iberian Pyrite Belt: the Perrrunal and Poderosa mines (SW of Spain). The REE patterns and Ce and Eu anomalies of the rock leachates have confirmed the geochemical relationship between the AMD and certain country rocks (felsic and mafic volcanics, and shales). A detailed chemical and mineralogical study has confirmed the existence of a diversity of minerals with high concentrations of REE. Thus, the minerals with the highest REE contents are also those with the fast dissolution kinetics under acid conditions: REE phosphates (monazite and xenotime type) and carbonates (parisite type). Finally, petrographic evidence of the selective leaching of these minerals clearly supports these minerals as the main source of REE in the AMD.This work was supported by the Spanish Ministry of Economy and Competitiveness through the research project TRAMPA (MINECO; PID2020-119196RB-C21). Funding for open access charge: Universidad de Huelva / CBUA

Wildfire effects on the hydrogeochemistry of a river severely polluted by acid mine drainage

This study evaluates for the first time the impact of a large wildfire on the hydrogeochemistry of a deeply AMDaffected river at the beginning of the wet season. To accomplish this, a high-resolution water monitoring campaign was performed within the basin coinciding with the first rainfalls after summer. Unlike similar events recorded in AMD-affected areas, where dramatic increases in most dissolved element concentrations, and decreases in pH values are observed as a result of evaporitic salts flushing and the transport of sulfide oxidation products from mine sites, a slight increase in pH values (from 2.32 to 2.88) and decrease in element concentrations (e.g.; Fe: 443 to 205 mg/L; Al: 1805 to 1059 mg/L; sulfate: 22.8 to 13.3 g/L) was observed with the first rainfalls after the fire. The washout of wildfire-ash deposited in the riverbanks and the drainage area, constituted by alkaline mineral phases, seems to have counterbalanced the usual behavior and patterns of the river hydrogeochemistry during autumn. Geochemical results indicate that a preferential dissolution occurs during ash washout (K > Ca > Na), with a quick release of K followed by an intense dissolution of Ca and Na. On the other hand, in unburnt zones parameters and concentrations vary to a lesser extent than burnt areas, being the washout of evaporitic salts the dominant process. With subsequent rainfalls ash plays a minor role on the river hydrochemistry. Elemental ratios (Fe/SO4 and Ca/Mg) and geochemical tracers in both ash (K, Ca and Na) and AMD (S) were used to prove the importance of ash washout as the dominant geochemical process during the study period. Geochemical and mineralogical evidences point to intense schwertmannite precipitation as the main driver of reduction in metal pollution. The results of this study shed light on the response of AMD-polluted rivers to certain climate change effects, since climate models predict an increase in the number and intensity of wildfires and torrential rain events, especially in Mediterranean climates.This research was supported by the AIHODIEL project (PYC20 RE 032 UHU) within the 2020 call for grants for the implementation of projects of collaborative interest in the field of innovation ecosystems co-financed by the FEDER program in Andalucía for the period 2014-2020. Jonatan Romero is financed by a FPU program of the Spanish Ministry of Education of Vocational Training (FPU20/04441). C.R Cánovas thanks the Spanish Ministry of Science and Innovation for the Postdoctoral Fellowship granted under application reference RYC2019–027949-I. Funding for open access charge: Universidad de Huelva / CBUA. The authors gratefully appreciate the constructive comments and suggestions from the editor Mark van Loosdrecht and two anonymous reviewers

Thallium in environmental compartments affected by acid mine drainage (AMD) from the Iberian Pyrite Belt (IPB): From rocks to the ocean

This works investigates the origin, behavior and fate of Tl in acid mine drainage (AMD) affected areas at catchment scale, following the path from rocks to the ocean. To address this issue, comprehensive data set of Tl in rocks, waters, secondary minerals, plants and other environmental compartments is presented, using the Iberian Pyrite Belt (SW Spain) as representative example. The content of Tl in host rocks (mean of 0.51 mg/kg) exhibits moderate positive correlations with elements such as K and Rb, whereas no correlations were observed in sulfides (27 mg/kg) between Tl, Fe and other metal/loids commonly found in these minerals, such as As, Pb, Cd, Cu or Zn. During sulfide oxidation processes, Tl is mobilized from sulfides, as evidenced by the depletion of Tl in gossans (1.8 mg/kg), and host rock minerals, leading to a Tl enrichment in AMD leachates (mean of 242 μg/L), with concentrations of up to 8.3 mg/L, several orders of magnitude higher than those reported in natural waters. The precipitation of secondary minerals, with large surface areas, may be a sink for Tl, especially in jarosite minerals (8.4 mg/kg). Thallium can be also removed during the treatment of AMD in alkaline passive treatment systems due mainly to sorption processes onto Fe and Al secondary minerals (i.e., schwertmannite and basaluminite, respectively). Mean Tl contents of 13 mg/kg have been observed in wastes dumped in abandoned mines of the IPB, mainly spoil heaps, slags, roasted pyrite, heap leaching wastes and tailings. However, there is no clear relationship between Tl content and the type of mining wastes. These wastes can suffer weathering, leading to an enrichment of Tl in soils. Previous studies reported that <25% of total Tl is easily extractable, being mainly adsorbed to crystalline Fe oxides in acidic soils and Al oxides in neutral-alkaline soils. Despite this, Tl may be translocated by plants. The translocation of Tl in plants of the IPB has not been properly addressed, however previous studies in other areas showed a low phytoavailability of Tl compared to Cd and Zn, although Tl translocation appears to be strongly controlled by plant species or by differences in Tl speciation. The weathering of rocks, mine wastes and soils may lead to the release of notable amounts of both dissolved and particulate Tl to the hydrosphere. In acidic conditions, Tl seems to be mainly transported by the dissolved phase in AMD-affected streams and rivers, with <15% being transported by the particulate matter. This latter Tl transport may be associated to its incorporation into diatoms and Fe minerals such as jarosite after replacement of Tl+ by H+ in their structure. Subsequent release by desorption processes from jarosite and diatoms in acidic conditions can occur. This process has also been observed in estuaries affected by AMD, thus, Tl transported by jarosite minerals in the particulate matter and diatoms are released back to the estuarine waters across the salinity gradient due to the increasing proportion of unreactive TlCl0 and K+ ions, which compete for adsorption sites in jarosite with Tl+. Thus, enhanced transport of Tl to the oceans is observed in AMD-affected systems.This work was supported by the Spanish Ministry of Economy and Competitiveness under the research project TRAMPA (MINECO; PID2020-119196RB-C21) and the Andalusian Regional Government under the AIHODIEL project (PYC20 RE 032 UHU) within the FEDER program. C.R Canovas thanks the Spanish Ministry of Science and Innovation for the Postdoctoral Fellowship granted under application reference RYC2019-027949-I. M.D. Basallote thanks the Spanish Ministry of Science and Innovation for the Postdoctoral Fellowship granted under application reference IJC2018-035056-I. Funding for open access charge: Universidad de Huelva /CBU

Metal(loid) release from sulfide-rich wastes to the environment: The case of the Iberian Pyrite Belt (SW Spain)

Sulfide-mining wastes may lead to severe environmental and human health risks, especially challenging in abandoned mines without environmental regulation. This work is aimed at discussing the environmental problems associated with this type of wastes, the risks posed by metal(loid) exposure to living organisms, as well as the measures available to mitigate such risks, taking the case of the Iberian Pyrite Belt (SW Iberian Peninsula), as an example, worldwide. The release of metal(loid)s from these wastes upon weathering is strongly controlled by mineral assemblage, processing technique, grain size distribution, and occurrence of highly reactive secondary minerals. Exposure to these wastes may pose a severe risk for humans and animals, and thus, remediation measures must be adopted in abandoned mines. Among these measures, recovery of valuable metals from sulfide wastes could be a promising environmentally friendly solution; however, grade and mineralogical siting of valuable metals, as well as selective recovery methods, must be site-by-site investigated.This work was supported by the Spanish Ministry of Economy and Competitiveness through the research projects SCYRE (CGL2016-78783- C2-1-R) and CAPOTE (CGL2017-86050-R). C.R Ca ́novas and M.D. Basallote thank the Spanish Ministry of Science and Innovation for the Postdoctoral Fellowships granted under application references RYC2019- 027949-I and IJC2018-035056-I, respectively. F. Macı ́as was funded by the R&D FEDER Andalucı ́a 2014e2020 call through the project RENOVAME (FEDER; UHU-1255729). The authors would like to thank to the Guest Editor Dr. Georgios Bartzas and two anonymous reviewers for their helpful comments that notably improved the quality of the original manuscript.Funding for open access charge: Universidad de Huelva / CBU

TARGETING IMMUNE-DRIVEN OPIOID ANALGESIA BY SIGMA-1 RECEPTORS: OPENING THE DOOR TO NOVEL PERSPECTIVES FOR THE ANALGESIC USE OF SIGMA-1 ANTAGONISTS

Immune cells have a known role in pronociception, since they release a myriad of inflammatory algogens which interact with neurons to facilitate pain signaling. However, these cells also produce endogenous opioid peptides with analgesic potential. The sigma-1 receptor is a ligand-operated chaperone that modulates neurotransmission by interacting with multiple protein partners, including the µ-opioid receptor. We recently found that sigma-1 antagonists are able to induce opioid analgesia by enhancing the action of endogenous opioid peptides of immune origin during inflammation. This opioid analgesia is seen only at the inflamed site, where immune cells naturally accumulate. In this article we review the difficulties of targeting the opioid system for selective pain relief, and discuss the dual role of immune cells in pain and analgesia. Our discussion creates perspectives for possible novel therapeutic uses of sigma-1 antagonists as agents able to maximize the analgesic potential of the immune systemUniversity of GranadaMartín Escudero postdoctoral programFPU grants from the Spanish Ministry of Economy and Competitiveness (MINECO)Juan de la Cierva-Incorporación postdoctoral grant from MINECOMINECO [grant number SAF2016-80540-R]Junta de Andalucía (grant CTS109)FEDER fund

Urinary bladder sigma-1 receptors: A new target for cystitis treatment

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.phrs.2020.104724.No adequate treatment is available for painful urinary bladder disorders such as interstitial cystitis/bladder pain syndrome, and the identification of new urological therapeutic targets is an unmet need. The sigma-1 receptor (σ1-R) modulates somatic pain, but its role in painful urological disorders is unexplored. The urothelium expresses many receptors typical of primary sensory neurons (e.g. TRPV1, TRPA1 and P2X3) and high levels of σ1- R have been found in these neurons; we therefore hypothesized that σ1-R may also be expressed in the urothelium and may have functional relevance in this tissue. With western blotting and immunohistochemical methods, we detected σ1-R in the urinary bladder in wild-type (WT) but not in σ1-R-knockout (σ1-KO) mice. Interestingly, σ1-R was located in the bladder urothelium not only in mouse, but also in human bladder sections. The severity of histopathological (edema, hemorrhage and urothelial desquamation) and biochemical alterations (enhanced myeloperoxidase activity and phosphorylation of extracellular regulated kinases 1/2 [pERK1/2]) that characterize cyclophosphamide-induced cystitis was lower in σ1-KO than in WT mice. Moreover, cyclophosphamide-induced pain behaviors and referred mechanical hyperalgesia were dose-dependently reduced by σ1-R antagonists (BD-1063, NE-100 and S1RA) in WT but not in σ1-KO mice. In contrast, the analgesic effect of morphine was greater in σ1-KO than in WT mice. Together these findings suggest that σ1-R plays a functional role in the mechanisms underlying cyclophosphamide-induced cystitis, and modulates morphine analgesia against urological pain. Therefore, σ1-R may represent a new drug target for urinary bladder disorders.Spanish Ministry of Economy and Competitiveness (MINECO) SAF2016-80540-REuropean Regional Development Funds (ERDF), Junta de Andalucia grant CTS 109Esteve PharmaceuticalsInnovative Medicines Initiative 2 Joint Undertaking 777500European Union's Horizon 2020 research and innovation programmeEFPI

Application of the passive Dispersed Alkaline Substrate (DAS) remediation system to treat highly acidic and polluted phosphogypsum leachates

Este trabajo estudia la viabilidad de la tecnología conocida como Sustrato Alcalino Disperso (DAS) para el tratamiento pasivo de efluentes extremadamente ácidos y contaminantes procedentes de la balsa de fosfoyesos localizada sobre las marismas del río Tinto (Huelva, SO España). El estudio consiste en hacer fluir el agua ácida a través de una columna rellena con una mezcla de un reactivo alcalino (i.e. Ca(OH)2 ) disperso en una matriz inerte (i.e. virutas de madera) capaz de elevar el pH del lixiviado y precipitar los contaminantes disueltos. El sistema de tratamiento DAS-Ca(OH)2 logró la retirada total de PO4 , F, Fe, Zn, Al, Cr, U y As de las soluciones. La precipitación de brushita [CaHPO4 ∙2H2 O] y yeso [CaSO4 ·2H2 O] fue el principal mecanismo responsable de la eliminación de los contaminantes. Los sólidos retenidos en la columna DAS después del tratamiento fueron sometidos al test de lixiviación EN 12457-2 de la EU para su clasificación y gestión de acuerdo a su peligrosidad. Algunos de estos sólidos podrían ser clasificados como residuos peligrosos, debido a la alta concentración de SO4 lixiviado. Este estudio contribuye al diseño de un tratamiento efectivo y sostenible de los lixiviados procedentes de la industria fertilizanteThis work studies the feasibility of the Dispersed Alkaline Substrate (DAS) technology for the passive treatment of highly acidic and polluted effluents from the phosphogypsum stack located on the Tinto river marsh soils (Huelva, SW Spain). The study consists of flowing the acidic water through a column filled with a mixture of an alkaline reagent (i.e. Ca(OH)2 ) scattered on an inert matrix (i.e. wood chips) capable of raising the pH of the leachate and precipitating the dissolved pollutants. The Ca(OH)2 -DAS treatment system achieved the total removal of PO4 , F, Fe, Zn, Al, Cr, U and As from the solutions. The precipitation of brushite [CaHPO4 ∙2H2 O] and gypsum [CaSO4 ∙2H2 O] seems to be the main mechanism responsible for the removal of contaminants. The solids collected from the DAS column were subjected to the EU EN 12457-2 leaching test for their classification and management according to their hazardousness. Some of these solids could be classified as hazardous wastes due to the high release of SO4 . This study may contribute to the design of an effective and sustainable treatment of leachates from the fertilizer industr

Mineral reactivity in sulphide mine wastes: influence of mineralogy and grain size on metal release

The aqueous oxidation of sulphide minerals leads to the generation of acid mine drainage (AMD), one of the main causes of water pollution worldwide. Mineral reactivity is greatly enhanced as a result of extraction and processes such as blasting, crushing, and grinding that increase rock surface area. The exposition of sulphide mine wastes to atmospheric conditions enhances AMD generation. However, a large number of processes and factors (e.g., pH, redox conditions, aqueous and surface complexation reactions) may control the mobility of elements in solution. In particular, the formation of soluble secondary minerals may act as transient storage of metals and acidity during AMD generation, leading however to their release upon rainfalls. To study the influence of mineralogy and grain size on the metal release from a variety of sulphide mine wastes collected in the Iberian Pyrite Belt, different grain size samples were treated with distilled water (S:L ratio 1:10) for 24 h simulating rainfall weathering. Results reveal that grain size plays a major role on metal mobility from sulphide mine wastes. However, mineralogical and geochemical evidence points at the partitioning of highly soluble secondary minerals among grain size fractions as the key factor controlling the metal release rate from these wastes. The results obtained show the importance of grain size on the reliability of the different leaching test procedures, and thus encourage standardizing these procedures worldwide.The authors thank two anonymous reviewers for helpful comments that clearly improved the quality of the manuscript, and Associate Editor Encarnación Ruiz-Agudo and Chief Editor Carlos Rodriguez-Navarro for their handling. This work was supported by the Spanish Ministry of Economic and Competitiveness through the projects CGL2016-78783-C2-1-R (SCYRE) and ERAMIN PCIN2015-242. C.R. Cánovas was funded by the Talent Consolidation Program of the University of Huelva. MD Basallote also thanks the Spanish Ministry of Economy and Competitiveness for the Postdoctoral Fellowship granted under application reference FJCI-2015-24765

Metal/loid release from cyanidation wastes in response to rainfalls

Cyanide heap leach operations developed in Tharsis (SW Spain) from 1982 to 2001 left the legacy of a huge amount of cyanidation wastes deposited over a total area of 47 ha without any type of isolation. The main goals of this work are to study the release of metals and metalloids under rainfall occurrence and the potential impact on the aquatic life. A vertical profile was sampled in the leaching heap and the chemical and mineralogical composition of these wastes was analyzed. In addition, the response of these wastes to rainfalls was studied by leaching with water at different solid-liquid ratios. The cyanidation wastes are mainly composed by Fe oxides/oxyhydroxides (i.e. goethite and hematite), oxyhydroxysulfates (i.e. jarosite), and quartz as well as gypsum in different levels. Although the alkaline conditions of the cyanidation wastes precluded the mobilization of most metals, some elements such as As, Zn, Ni and Pb showed concentrations which may pose a significant risk to aquatic life if chronic exposure is maintained. For this reason, a safe disposal of these wastes is needed in order to reduce the release of metals into the environment