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

Endocrine Disrupting Chemicals in Cosmetics and Personal Care Products and Risk of Endometriosis

In the last years, the variety and consumption of cosmetics and personal care products (PCPs) have greatly increased, although the long-term adverse effects to low doses of chemicals used in their production and with proven hormone-mimicking properties have been still poorly addressed. Among these endocrine disrupting chemicals (EDCs), parabens, benzophenones, bisphenols, and phthalates are the most widely found in these products. Given the estrogenic-dependent nature of the endometrium, it has been hypothesized the potential contribution of these EDCs contained in cosmetics and PCPs in the risk of endometriosis. In this book chapter, we have summarized the current evidence supporting this hypothesis, highlighting epidemiological, in vivo, and in vitro studies that have addressed the potential influence of parabens, benzophenones, bisphenols, and phthalates in the origin and progression of this chronic feminine disease

Circadian Regulation of Colon Cancer Stem Cells: Implications for Therapy

The presence of cancer stem cells (CSCs) in colorectal cancer (CRC) has been associated with tumor initiation, metastasis, relapse, and resistance to chemotherapy and radiotherapy. Therefore, a better knowledge of the molecular mechanisms involved in the regulation of CSCs is required to develop treatments that are more effective. Like normal cells, cancer cells contain molecular clocks that generate circadian rhythms in gene expression and metabolic activity. Disruption of circadian rhythms has been linked to increased cancer risk, chemoresistance, and progression in CRC. CSCs also generate rhythms, which could be exploited with a chronopharmacological approach. Although the regulation of the expression of circadian rhythm genes appears to be mediated mainly by transcription–translation feedback loops, the existence of forms of nontranscriptional regulation has been demonstrated. Particularly, microRNAs (miRNA) and SIRT1 are significant players in regulating various aspects of the circadian clock function. Furthermore, miRNA acts as a regulator of cancer progression by regulating the CSC characteristics through SIRT1. These findings led us to hypothesize that there is a circadian rhythm of CSC markers regulated by miRNAs in CRC with SIRT1 acting as a mediator of miRNA activity. The pharmacological regulation of SIRT1, and therefore of the circadian machinery, could result in antiproliferative effects and increased sensitivity to antitumor treatments in CRC

Effects of Tetrodotoxin in Mouse Models of Visceral Pain

Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptor‑specific Nav1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Nav1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain.R. González-Cano was supported by a postdoctoral grant from the Contratos-Puente Research Program of the University of Granada. M.A. Tejada was supported by a predoctoral grant from the University of Granada. F. R. Nieto was supported by a postdoctoral Juan de la Cierva grant (Spanish Goverment). This study was partially supported by grant GREIB (CEB-005) from the University of Granada and grant CTS 109 from the Junta de Andalucía

Associations of persistent organic pollutants in human adipose tissue with retinoid levels and their relevance to the redox microenvironment

This work was supported by research grants from CIBER de Epidemiologia y Salud Publica (CIBERESP), Instituto de Salud Carlos III, Junta de Andalucia, European Regional Development Fund-FEDER (PI16/01858, PI16/01812, PI20/01568 and PI-13/02406) and Generalitat Valenciana. Dr. G Cakmak is awarded a grant by The Scientific and Technological Research Council of Turkey (TUBITAK-2219). Dr. JP Arrebola is under contract within the Ramón y Cajal Program (RYC-2016-20155, Ministerio de Economia, Industria y Competitividad, Spain).These results would not have been achieved without the selfless collaboration of the staff from Santa Ana and San Cecilio Hospitals and the participants who took part in the study.Humans are exposed to a myriad of chemical substances in both occupational and environmental settings. Persistent organic pollutants (POPs) have drawn attention for their adverse effects including cancer and endocrine disruption. Herein, the objectives were 1) to describe serum and adipose tissue retinol levels, along with serum retinol binding protein 4 (RBP4) concentrations, and 2) to assess the associations of adipose tissue POP levels with these retinoid parameters, as well as their potential interaction with the previously-observed POP-related disruption of redox microenvironment. Retinol was measured in both serum and adipose tissue along with RBP4 levels in serum samples of 236 participants of the GraMo adult cohort. Associations were explored by multivariable linear regression analyses and Weighted Quantile Sum regression. Polychlorinated biphenyls (PCBs) 180, 153 and 138 were related to decreased adipose tissue retinol levels and increased serum RBP4/retinol ratio. Dicofol concentrations > limit of detection were associated with decreased retinol levels in serum and adipose tissue. Additionally, increased adipose tissue retinol levels were linked to an attenuation in previously-reported associations of adipose tissue PCB-153 with in situ superoxide dismutase activity. Our results revealed a suggestive link between retinoids, PCBs and redox microenvironment, potentially relevant for both mechanistic and public health purposes.CIBER de Epidemiologia y Salud Publica (CIBERESP)Instituto de Salud Carlos III, Junta de AndaluciaEuropean Commission PI16/01858 PI16/01812 PI20/01568 PI-13/02406Generalitat ValencianaEuropean CommissionTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) TUBITAK-2219Ramon y Cajal Program (Ministerio de Economia, Industria y Competitividad, Spain) RYC-2016-2015

Chronic Fatigue, Physical Impairments and Quality of Life in Women with Endometriosis: A Case-Control Study

The authors are indebted with all participants, without whom this work would not have been possible. We are grateful to Ana Yara Postigo-Fuentes for her assistance with the English language. This paper is part of the PhD thesis developed by A. Lara-Ramos in the Official Doctoral Programme in Clinical Medicine and Public Health of the University of Granada.Aim: To explore endometriosis-related fatigue (ERF), health-related fitness, sleep quality, and health-related quality of life (HRQoL) in women with endometriosis in comparison with matched controls. Methods: Twenty-five affected women and twenty-five age and height-matched women without endometriosis were included. ERF was assessed through the Piper Fatigue Scale; health-related fitness was assessed through the Schöber, flamingo, and 6-min walking tests and dynamometry; and body composition was assessed through impedanciometry. Self-perceived physical fitness, sleep quality, and HRQoL were assessed through the International Fitness Scale, the Pittsburgh Sleep Quality Index, and the 12-item Short Form Health Survey, respectively. Results: Affected women exhibited higher levels of ERF than controls, increased fat mass, and physical deconditioning (reduced back strength, lumbar flexibility, body balance, and functional capacity, p-values < 0.050). Moreover, cases also had poorer perceived physical fitness, sleep quality, and HRQoL (p-value < 0.050). Finally, we observed deteriorated health-related fitness, sleep quality, and HRQoL in those women with endometriosis with higher levels of ERF. Conclusions: This study constitutes the first evidence that women with endometriosis describe a generalized physical deconditioning, even more pronounced in affected women with higher levels of ERF. Further studies assessing the efficacy of rehabilitation interventions to face these physical impairments in women with endometriosis are warranted.Health Institute Carlos III (ISCIII)-FEDER PI17/01743PAIDI group CTS-206University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES)Junta de AndaluciaConsejeria de Conocimiento, Investigacion y UniversidadesEuropean Union (EU) SOMM17/6107/UG

Exposure to non-persistent pesticides, BDNF, and behavioral function in adolescent males: Exploring a novel effect biomarker approach

This research would not have been achieved without the selfless collaboration of the INMA-Granada adolescents and families who took part in the study. The authors acknowledge the European Union's Horizon 2020 research and innovation program HBM4EUfor the financial support under Grant Agreement #733032. The study was also supported by the ISCIII with grants no. CP16/00085 and FIS 17/01526, and the Human Genotyping Laboratory at the Spanish National Cancer Research Center (CeGen-PRB3). The authors also thank the support of the Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP), and the University of Granada (Grant "UNETE," UCE-PP2017-06). A. Rodriguez-Carrillo received a predoctoral fellowship (FPU 16/03011) from the Spanish Ministry of Education, Spain, and Vicente Mustieles and Shereen Cynthia D'Cruz were under contract with the HBM4EUproject. C. Freire received a grant under the Miguel Servet Type I program of the ISCIII "Fondo Europeo de Desarrollo Regional" (MS16/00085; ISCIII/FEDER). This article forms part of the doctoral thesis developed by Andrea Rodriguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain).Background: Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological function that could help to understand the biological responses of some environmental exposures. Objectives: To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents. Methods: The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide carbaryl 1-naphthol (1-N), and the metabolite of ethylene-bis-dithiocarbamate fungicides ethylene thiourea (ETU) were measured in spot urine samples, as well as serum BDNF protein levels and blood DNA methylation of Exon IV of BDNF gene in 15–17-year-old boys from the INMA-Granada cohort in Spain. Adolescents’ behavior was reported by parents using the Child Behavior Check List (CBCL/ 6–18). This study included 140 adolescents of whom 118 had data on BDNF gene DNA methylation. Multivariable linear regression, weighted quantile sum (WQS) for mixture effects, and mediation models were fit. Results: IMPy, MDA, DCCA, and ETU were detected in more than 70% of urine samples, DETP in 53%, and TCPy, 3-PBA, and 1-N in less than 50% of samples. Higher levels of IMPy, TCPy, and ETU were significantly associated with more behavioral problems as social, thought problems, and rule-breaking symptoms. IMPy, MDA, DETP, and 1-N were significantly associated with decreased serum BDNF levels, while MDA, 3-PBA, and ETU were associated with higher DNA methylation percentages at several CpGs. WQS models suggest a mixture effect on more behavioral problems and BDNF DNA methylation at several CpGs. A mediated effect of serum BDNF within IMPy-thought and IMPy-rule breaking associations was suggested. Conclusion: BDNF biomarkers measured at different levels of biological complexity provided novel information regarding the potential disruption of behavioral function due to contemporary pesticides, highlighting exposure to diazinon (IMPy) and the combined effect of IMPy, MDA, DCCA, and ETU. However, further research is warranted.European Union's Horizon 2020 research and innovation program HBM4EU 733032Instituto de Salud Carlos III CP16/00085 FIS 17/01526Human Genotyping Laboratory at the Spanish National Cancer Research Center (CeGen-PRB3)Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP)University of Granada UCE-PP2017-06Spanish Government FPU 16/03011Miguel Servet Type I program of the ISCIII "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) MS16/0008

Radiation and Stemness Phenotype May Influence Individual Breast Cancer Outcomes: The Crucial Role of MMPs and Microenvironment

Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor developmentThis research was funded by the FUNDACIÓN PROGRESO Y SALUD, Consejería de Igualdad, Salud y Políticas Sociales, Junta de Andalucía (PI-730), the INSTITUTO DE SALUD CARLOS III, Ministerio de Ciencia, Innovación y Universidades (PIE16-00045) and by the Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963)

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

‘Physio-EndEA’ Study: A Randomized, Parallel-Group Controlled Trial to Evaluate the Effect of a Supervised and Adapted Therapeutic Exercise Program to Improve Quality of Life in Symptomatic Women Diagnosed with Endometriosis

This research was funded by the Health Institute Carlos III (FEDER funds), grant number PI17/01743, and donations from particular endometriosis women that believed in this project from the beginning. It was also partly supported by funds from the PAIDI group CTS-206 (Oncologia Basica y Clinica). This study takes place thanks to the additional funding from the University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES).Aim: The ‘Physio-EndEA’ study aims to explore the potential benefits of a therapeutic exercise program (focused on lumbopelvic stabilization and tolerance to exertion) on the health-related quality of life (HRQoL) of symptomatic endometriosis women. Design: The present study will use a parallel-group randomized controlled trial design. Methods: A total of 22 symptomatic endometriosis women will be randomized 1:1 to the Physio-EndEA or usual care groups. The ‘Physio-EndEA’ program will consist of a one-week lumbopelvic stabilization learning phase followed by an eight-week phase of stretching, aerobic and resistance exercises focused on the lumbopelvic area that will be sequentially instructed and supervised by a trained physiotherapist (with volume and intensity progression) and adapted daily to the potential of each participant. The primary outcome measure is HRQoL. The secondary outcome measures included clinician-reported outcomes (pressure pain thresholds, muscle thickness and strength, flexibility, body balance and cardiorespiratory fitness) and patient-reported outcomes (pain intensity, physical fitness, chronic fatigue, sexual function, gastrointestinal function and sleep quality). Discussion: Findings of this study will help to identify cost-effective non-pharmacological options (such as this exercise-based intervention) that may contribute to the improvement of HRQoL in symptomatic endometriosis women.Health Institute Carlos III (FEDER funds) PI17/01743PAIDI groupUniversity of Granad